EP2445906A1 - Insecticidal compounds - Google Patents

Insecticidal compounds

Info

Publication number
EP2445906A1
EP2445906A1 EP10726052A EP10726052A EP2445906A1 EP 2445906 A1 EP2445906 A1 EP 2445906A1 EP 10726052 A EP10726052 A EP 10726052A EP 10726052 A EP10726052 A EP 10726052A EP 2445906 A1 EP2445906 A1 EP 2445906A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
phenyl
methyl
independently
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP10726052A
Other languages
German (de)
French (fr)
Other versions
EP2445906B1 (en
Inventor
Peter Renold
Jérôme Yves CASSAYRE
Myriem El Qacemi
Jagadish Pabba
Thomas Pitterna
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Syngenta Participations AG
Syngenta Ltd
Original Assignee
Syngenta Participations AG
Syngenta Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0910767A external-priority patent/GB0910767D0/en
Priority claimed from GB0910768A external-priority patent/GB0910768D0/en
Priority claimed from PCT/EP2009/059563 external-priority patent/WO2010020522A1/en
Application filed by Syngenta Participations AG, Syngenta Ltd filed Critical Syngenta Participations AG
Priority to EP10726052.3A priority Critical patent/EP2445906B1/en
Publication of EP2445906A1 publication Critical patent/EP2445906A1/en
Application granted granted Critical
Publication of EP2445906B1 publication Critical patent/EP2445906B1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • the present invention relates to certain dihydro -pyrrole derivatives with a four- membered ring as terminal group, to processes and intermediates for preparing these derivatives, to insecticidal, acaricidal, nematicidal and molluscicidal compositions comprising these derivatives and to methods of using these derivatives to control insect, acarine, nematode and mollusc pests.
  • dihydro-pyrrole derivatives with insecticidal properties are disclosed in, for example, JP 2007/091708 and JP 2008/133273. It has now surprisingly been found that dihydro-pyrrole derivatives with a four- membered ring as terminal group have insecticidal properties.
  • the present invention therefore provides a compound of formula (I)
  • a 1 , A 2 , A 3 and A 4 are independently of each other C-H, C-R 5 or nitrogen; G is oxygen or sulfur;
  • R 1 is hydrogen, Ci-Csalkyl, Ci-Csalkoxy-, Ci-Csalkylcarbonyl- or Ci-Csalkoxycarbonyl-;
  • R 2 is a group of formula (II)
  • L is a single bond or Ci-C ⁇ alkylene
  • R 4 is aryl or aryl substituted by one to five R 7 , or heteroaryl or heteroaryl substituted by one to five R 7 ; each R 5 is independently halogen, cyano, nitro, Ci-Csalkyl, Ci-Cshaloalkyl, Ci-Csalkenyl, Ci-Cshaloalkenyl, Ci-Csalkynyl, Ci-Cshaloalkynyl, C 3 -Ciocycloalkyl, Ci-Csalkoxy-, Ci- C 8 haloalkoxy-, Ci-C 8 alkylthio-, Ci-Cghaloalkylthio-, Ci-C 8 alkylsulfmyl-, Ci-C 8 haloalkyl- sulf ⁇ nyl-, Ci-Csalkylsulfonyl- or Ci-Cshaloalkylsulfonyl-, or two R 5 on adjacent carbon atoms together form a
  • each R 8 and R 9 is independently hydrogen, halogen, Ci-Csalkyl or Ci-Cshaloalkyl
  • the compounds of the invention may contain one or more asymmetric carbon atoms, for example, at the -CR 3 R 4 - group, and may exist as enantiomers (or as pairs of diastereo- isomers) or as mixtures of such.
  • Alkyl groups can be in the form of a straight or branched chain and are, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but- 2-yl, 2-methyl-prop-l-yl or 2-methyl-prop-2-yl.
  • the alkyl groups are, unless indicated to the contrary, preferably Ci-C 6 , more preferably C 1 -C 4 , most preferably C 1 -C3 alkyl groups.
  • Alkylene groups can be in the form of a straight or branched chain and are, for example, -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -, or -CH(CH 2 CH 3 )-.
  • the alkylene groups are, unless indicated to the contrary, preferably Ci-C 3 , more preferably Ci-C 2 , most preferably Ci alkylene groups.
  • Alkenyl groups can be in the form of straight or branched chains, and can be, where appropriate, of either the (E)- or (Z)-conf ⁇ guration. Examples are vinyl and allyl.
  • alkenyl groups are, unless indicated to the contrary, preferably C 2 -C 6 , more preferably C2-C4, most preferably C2-C3 alkenyl groups.
  • Alkynyl groups can be in the form of straight or branched chains. Examples are ethynyl and propargyl.
  • the alkynyl groups are, unless indicated to the contrary, preferably C 2 -C 6 , more preferably C2-C4, most preferably C2-C3 alkynyl groups.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • Haloalkyl groups are alkyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, difluoromethyl, trifluoromethyl, chlorodifluoromethyl or 2,2,2-trifluoro-ethyl.
  • Haloalkenyl groups are alkenyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, 2,2-difluoro-vinyl or l,2-dichloro-2- fluoro-vinyl.
  • Haloalkynyl groups are alkynyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, l-chloro-prop-2-ynyl.
  • Cycloalkyl groups can be in mono- or bi-cyclic form and are, for example, cyclopropyl, cyclobutyl, cyclohexyl and bicyclo[2.2.1]heptan-2-yl.
  • the cycloalkyl groups are, unless indicated to the contrary, preferably C3-C8, more preferably C 3 -C 6 cycloalkyl groups.
  • Aryl groups are aromatic ring systems which can be in mono-, bi- or tricyclic form. Examples of such rings include phenyl, naphthyl, anthracenyl, indenyl or phenanthrenyl. Preferred aryl groups are phenyl and naphthyl, phenyl being most preferred. Where an aryl moiety is said to be substituted, the aryl moiety is, unless indicated to the contrary, preferably substituted by one to four substituents, most preferably by one to three substituents.
  • Heteroaryl groups are aromatic ring system containing at least one heteroatom and consisting either of a single ring or of two or more fused rings.
  • single rings will contain up to three heteroatoms and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur.
  • monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl.
  • bicyclic groups include quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl and benzothiazolyl.
  • Monocyclic heteroaryl groups are preferred, pyridyl being most preferred.
  • the heteroaryl moiety is, unless indicated to the contrary, preferably substituted by one to four substituents, most preferably by one to three substituents.
  • Heterocyclyl groups are defined to include heteroaryl groups and in addition their unsaturated or partially unsaturated analogues.
  • monocyclic groups include thietanyl, pyrrolidinyl, tetrahydrofuranyl, [l,3]dioxolanyl, piperidinyl, piperazinyl, [l,4]dioxanyl, and morpholinyl or their oxidised versions such as 1-oxo -thietanyl and 1,1- dioxo -thietanyl.
  • bicyclic groups examples include 2,3-dihydro-benzofuranyl, benzo[l,3]dioxolanyl, and 2,3-dihydro-benzo[l,4]dioxinyl.
  • a heterocyclyl moiety is said to be substituted, the heterocyclyl moiety is, unless indicated to the contrary, preferably substituted by one to four substituents, most preferably by one to three substituents.
  • a 1 , A 2 , A 3 , A 4 , G, R 1 , R 2 , R 3 , R 4 , L, Y 1 , Y 2 , Y 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and m are, in any combination, as set out below.
  • a 1 , A 2 , A 3 and A 4 are nitrogen.
  • a 1 is C-H or C-R 5 , most preferably A 1 is C-R 5 .
  • a 2 is C-H or C-R 5 , most preferably A 2 is C-H.
  • a 3 is C-H or C-R 5 , most preferably A 3 is C-H.
  • a 4 is C-H or C-R 5 , most preferably A 4 is C-H.
  • a 1 , A 2 , A 3 and A 4 are independently of each other C-H or C-R 5 .
  • a 1 is C-R 5
  • a 2 is C-H
  • a 3 is C-H or nitrogen
  • a 4 is C-H or nitrogen.
  • a 1 is C-R 5
  • a 2 is C-H
  • a 3 is C-H or nitrogen
  • a 4 is C-H.
  • a 1 is C-R 5
  • a 2 is C-H
  • a 3 is C-H
  • a 4 is C-H.
  • G is oxygen.
  • R 1 is hydrogen, methyl, ethyl, methylcarbonyl- or methoxycarbonyl-, more preferably hydrogen, methyl or ethyl, most preferably hydrogen.
  • R 2 is a group of formula (Ha)
  • L is a single bond, methylene, ethylene or propylene
  • R 13 is Ci-C 8 alkyl
  • m is O, 1, 2, 3, 4, or 5
  • L is a single bond, methylene, ethylene or propylene
  • R 13 is hydrogen or d-Cgalkyl, e.g. d-Cgalkyl
  • R 2 is a group of formula (lie)
  • R 13 is d-Cgalkyl, preferably methyl
  • m is O, 1, 2, 3, 4, or 5
  • YY 22 iiss SS,, SSOO,, SO 2
  • S N-R 10
  • R 2 is a group of formula (Hd)
  • R , 13 is hydrogen or Ci-Csalkyl, e.g. Ci-Csalkyl, e.g. hydrogen or methyl
  • R 2 is thietan-3-yl-, l-oxo-thietan-3-yl-, l,l-dioxo-thietan-3-yl- or 3- methyl-thietan-3 -yl- .
  • R 2 is a group of formula (Hc')
  • R 2 is a group of formula (Hd')
  • R 3 is chlorodifluoromethyl or trifluoromethyl, most preferably trifluoro- methyl.
  • R 4 is phenyl or phenyl substituted by one to five R 7 , more preferably phenyl substituted by one to three R 7 , even more preferably R 4 is 3,5-dibromo-phenyl-, 3,5- dichloro -phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-, 3,4-dichloro-phenyl-, 3,4,5-trichloro- phenyl- or 3-trifluoromethyl-phenyl-, most preferably 3,5-dichloro-phenyl.
  • L is a single bond, methylene, ethylene or propylene. More preferably L is methylene or a single bond. Even more preferably L is a single bond.
  • Y 1 is CR 8 R 9 , more preferably CH 2 .
  • Y 3 is CR 8 R 9 , more preferably CH 2 .
  • each R 5 is independently halogen, d-Cgalkyl, Ci-Cshaloalkyl or Ci-
  • R 6 is methyl or hydrogen.
  • each R 7 is independently halogen, cyano, Ci-Csalkyl, Ci-Cshaloalkyl or Ci-Csalkoxy-, more preferably bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy, preferably bromo, chloro or trifluoromethyl, most preferably bromo or chloro.
  • each R 8 is independently hydrogen or Ci-Csalkyl, more preferably hydrogen or methyl, most preferably hydrogen.
  • each R 9 is independently hydrogen or Ci-Csalkyl, more preferably hydrogen or methyl, most preferably hydrogen.
  • each R 10 is independently methyl, hydrogen or cyano, e.g. hydrogen or cyano, preferably methyl or hydrogen, e.g. hydrogen.
  • each R 11 is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro or methyl, most preferably chloro, fluoro or methyl.
  • each R 12 is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro or methyl, most preferably chloro, fluoro or methyl.
  • each R 13 is independently methyl.
  • m is 0 or 1, most preferably 0.
  • a group of preferred compounds are those wherein A 1 , A 2 , A 3 and A 4 are independently of each other C-H or C-R 5 , preferably A 1 is C-R 5 , A 2 is C-H, A 3 is C-H or nitrogen and A 4 is C-H or nitrogen; G is oxygen;
  • R 1 is hydrogen, methyl, ethyl, methylcarbonyl- or methoxycarbonyl-;
  • R 2 is a group of formula (Ha)
  • R 3 is Ci-C 8 haloalkyl;
  • a 1 , A 2 , A 3 and A 4 are independently of each other C-H or C-R 5 , preferably A 1 is C- R 5 , A 2 is C-H, A 3 is C-H and A 4 is C-H; G is oxygen;
  • R 1 is hydrogen, methyl or ethyl
  • R 2 is a group of formula (lib)
  • R 3 is chlorodifluoromethyl or trifluoromethyl
  • R 4 is 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-,
  • a 1 , A 2 , A 3 and A 4 are independently of each other C-H or C-R 5 , preferably A 1 is C-
  • R 5 A 2 is C-H, A 3 is C-H and A 4 is C-H; G is oxygen; R 1 is hydrogen; R 2 is a group of formula (lie)
  • R 13 is methyl
  • a further group of preferred compounds are those wherein A 1 is C-R 5 , A 2 is C-H, A 3 is C-H and A 4 is C-H; G is oxygen;
  • R 1 is hydrogen
  • R 2 is a group of formula (Hd)
  • Y 2 is S, SO, SO 2 ;
  • R 3 is trifluoromethyl;
  • R 4 is 3,5-dichloro-phenyl; each R 5 is independently methyl;
  • R 13 is hydrogen or methyl.
  • a compound of formula (Ia) where G, R 1 , R 2 , R 3 , R 4 and R 5 are as defined for a compound of formula (I); or a salt or TV- oxide thereof.
  • the preferred values of G, L, R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 , Y 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and m are as defined for a compound of formula (I).
  • G, R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I); or a salt or TV-oxide thereof.
  • the preferred values of G, L, R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 , Y 3 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and m are as defined for a compound of formula (I).
  • G, R 1 , R 2 , R 3 , R 4 and R 5 are as defined for a compound of formula (I); or a salt or TV- oxide thereof.
  • the preferred values of G, L, R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 , Y 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and m are as defined for a compound of formula (I).
  • a 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I); G is oxygen and R is Ci-C 6 alkoxy.
  • the preferences for A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are the same as the preferences set out for the corresponding substituents of a compound of formula
  • a further group of novel intermediates are compounds of formula (VA)
  • a 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I); R is Ci- C ⁇ alkoxy; and X A is a leaving group such as a halogen atom, preferably bromine or chlorine, more preferably bromine.
  • the preferences for A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are the same as the preferences set out for the corresponding substituents of a compound of formula (I).
  • a further group of novel intermediates are compounds of formula (XIA)
  • a 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I); each R is independently Ci-C ⁇ alkoxy; G is oxygen and X A is a leaving group such as a halogen atom, preferably bromine or chlorine, more preferably bromine.
  • the preferences for A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are the same as the preferences set out for the corresponding substituents of a compound of formula (I).
  • a further group of novel intermediates are compounds of formula (XVII)
  • a 1 , A 2 , A 3 , A 4 , R 1 and R 2 are as defined for a compound of formula (I), R 1 ', R 2 and R 3 ' are each independently optionally substituted alkyl or optionally substituted phenyl, preferably Ci-Cs alkyl, Ci-Cs haloalkyl, phenyl or phenyl optionally substituted with one to five groups independently selected from halogen and Ci-Cs alkyl, R 4 ' is optionally substituted phenyl, optionally substituted alkyl, preferably Ci-Cs alkyl or Ci-Cs haloalkyl.
  • the preferences for A 1 , A 2 , A 3 , A 4 , R 1 and R 2 are the same as the preferences set out for the corresponding substituents of a compound of formula (I).
  • a further group of novel intermediates are compounds of formula (XX)
  • a 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I).
  • the preferences for A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are the same as the preferences set out for the corresponding substituents of a compound of formula (I).
  • a further group of novel intermediates are compounds of formula (XXIV)
  • a 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I); and X A is a leaving group such as a halogen atom, preferably bromine or chlorine, more preferably bromine.
  • the preferences for A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are the same as the preferences set out for the corresponding substituents of a compound of formula (I).
  • a further group of novel intermediates are compounds of formula (XXVI)
  • a 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I);
  • the preferences for A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are the same as the preferences set out for the corresponding substituents of a compound of formula (I).
  • a further group of novel intermediates are compounds of formula (XXVII) wherein A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I); and X A is a leaving group such as a halogen atom, preferably bromine or chlorine, more preferably bromine.
  • the preferences for A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are the same as the preferences set out for the corresponding substituents of a compound of formula (I).
  • the compounds of the invention may be made by a variety of methods, for example, as shown in Scheme 1.
  • An amine of formula (IX) where A 1 , A 2 , A 3 and A 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom, can be made by reacting a benzonitrile of formula (X) where A 1 , A 2 , A 3 and A 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom, with a reducing agent, for example a metal hydride, such as lithium aluminum hydride, in a solvent, such as an aprotic solvent, such as diethyl ether.
  • a halogen atom such as a bromine atom
  • the reaction is carried out preferably under a protective atmosphere, such as an argon atmosphere.
  • the reaction is carried out preferably at a temperature of from -20 0 C to +100 0 C, more preferably from 0 0 C to 80 0 C, in particular at 40 0 C.
  • Benzonitriles of formula (X) are commercially available or can be made by methods known to a person skilled in the art.
  • a formamide of formula (VIII) where A 1 , A 2 , A 3 and A 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom, can be made by reacting an amine of formula (IX) as defined under 1), with a formylating agent, such as ethyl formate, in a solvent, for example an excess of the formylating agent, in the presence of a base, for example an organic base, such as triethylamine.
  • the reaction is carried out preferably at a temperature of from -20 0 C to +100 0 C, more preferably from 20 0 C to 90 0 C, in particular at the reflux temperature of the solvent.
  • An isocyano compound of formula (VII) where A 1 , A 2 , A 3 and A 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom, can be made by reacting a formamide of formula (VIII) as defined under 2), with a dehydrating agent, for example a chlorinating agent, such as phosphorus oxychloride, in a solvent, for example an aprotic solvent, such as dichloromethane. The reaction is carried out preferably at a temperature of from -20 0 C to +50 0 C, more preferably from 0 0 C to 50 0 C, in particular at ambient temperature.
  • a dehydrating agent for example a chlorinating agent, such as phosphorus oxychloride
  • a compound of formula (V) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom, can be made by reacting an isocyano compound of formula (VII) as defined under 3), with a vinyl compound of formula (VI) where R 3 and R 4 are as defined for a compound of formula (I), in the presence of a catalyst, such as copper(I) oxide, in a solvent, for example an aromatic solvent, such as toluene.
  • a catalyst such as copper(I) oxide
  • the reaction is carried out preferably at a temperature of from -20 0 C to +200 0 C, more preferably from 50 0 C to 150 0 C, in particular at 110 0 C.
  • Vinyl compounds of formula (VI) are known from the literature (for example, from EP 1 ,731 ,512) or can be made by methods known to a person skilled in the art.
  • a carboxylic ester of formula (IV) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I), G is oxygen and R is Ci-Csalkoxy can be made by reacting a compound of formula (V) as defined under 4), with carbon monoxide and an alcohol of formula R-H where R is Ci-Csalkoxy, such as ethanol, in the presence of a catalyst, such as bis(triphenylphosphine)palladium(II) dichloride (“Pd(PPh 3 )2Cl 2 ") or dichloro 1,1'- bis(diphenylphosphino)ferrocene palladium(II) dichloromethane adduct (“Pd(dppf)Cl2”), in the presence of a base, such as pyridine, triethylamine, 4-(dimethylamino)-pyridine (“DMAP”), diisopropylethylamine
  • the reaction is carried out preferably at a temperature of from -20 0 C to +200 0 C, more preferably from 50 0 C to 150 0 C, in particular at 85°C.
  • the reaction is carried out preferably at a pressure of from 1 to 200 bar, more preferably from 2 to 10 bar, in particular at 6 bar.
  • a carboxylic acid of formula (III) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I), G is oxygen and R is OH can be made from a carboxylic ester of formula (IV) as defined under 5), under standard conditions, such as treatment with an alkali hydroxide, such as sodium hydroxide or potassium hydroxide, in a solvent, such as ethanol or tetrahydrofuran, in the presence of water.
  • an alkali hydroxide such as sodium hydroxide or potassium hydroxide
  • a solvent such as ethanol or tetrahydrofuran
  • Another alternative is the treatment of the ester with an acid, such as trifluoroacetic acid, in a solvent, such as dichloromethane, followed by addition of water.
  • the reaction is carried out preferably at a temperature of from -20 0 C to +100 0 C, more preferably from 20 0 C to 80 0 C, in particular at 50
  • An acid halide of formula (III 1 ) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I), G is oxygen and R is Br, Cl or F, can be made from a carboxylic acid of formula (III) as defined under 5), under standard conditions, such as treatment with thionyl chloride or oxalyl chloride, in a solvent, such as dichloromethane.
  • the reaction is carried out preferably at a temperature of from -20 0 C to +100 0 C, more preferably from 0 0 C to 50 0 C, in particular at ambient temperature.
  • a compound of formula (I) where A , A , A , A , R , R and R are as defined for a compound of formula (I) and G is oxygen can be made by reacting a carboxylic acid of formula (III) or an acid halide of formula (III 1 ) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I) and G is oxygen, with an amine of formula HNR 1 R 2 where R 1 and R 2 are as defined for a compound of formula (I).
  • a carboxylic acid When a carboxylic acid is used, such reactions are usually carried out in the presence of a coupling reagent, such as N, N'- dicyclohexylcarbodiimide (“DCC”), 1 -ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (“EDC”) or bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”), in the presence of a base, and optionally in the presence of a nucleophilic catalyst.
  • DCC N, N'- dicyclohexylcarbodiimide
  • EDC 1 -ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride
  • BOP-Cl bis(2-oxo-3-oxazolidinyl)phosphonic chloride
  • Such reactions are carried out preferably at a temperature of from -20 0 C to +200
  • an acid halide When an acid halide is used, such reactions are usually carried out in the presence of a base, and optionally in the presence of a nucleophilic catalyst.
  • a base When an acid halide is used it is possible to conduct the reaction in a biphasic system comprising an organic solvent, preferably ethyl acetate, and an aqueous solvent, preferably a solution of sodium hydrogen carbonate.
  • Such reactions are carried out preferably at a temperature of from -20 0 C to +50 0 C, more preferably from 0 0 C to 50 0 C, in particular at ambient temperature.
  • Suitable nucleophilic catalysts include hydroxy- benzotriazole ("HOBT").
  • Suitable solvents include dimethylacetamide, tetrahydrofuran, dioxane, 1 ,2-dimethoxyethane, ethyl acetate and toluene.
  • Amines of formula (II) are known from the literature (for example, from WO 2007/080131) or can be made by methods known to a person skilled in the art.
  • a compound of formula (I) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I) and G is sulfur can be made by reacting a compound of formula (III) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I), G is oxygen, or a compound of formula (HF) wherein R is Br, Cl or F, or a compound of formula (XI) wherein R is Ci-Csalkoxy (see Scheme 2), with a thio-transfer reagent, such as Fawesson's reagent or phosphorus pentasulfide, prior to reacting with the amine of formula FFNR 1 R 2 as described under 8).
  • a thio-transfer reagent such as Fawesson's reagent or phosphorus pentasulfide
  • Such conditions are, for example, treatment with an alkali hydroxide, such as sodium hydroxide or potassium hydroxide, in a solvent, such as ethanol or tetrahydrofuran, in the presence of water.
  • an alkali hydroxide such as sodium hydroxide or potassium hydroxide
  • a solvent such as ethanol or tetrahydrofuran
  • Another alternative is the treatment of the ester with an acid, such as trifluoroacetic acid, in a solvent, such as dichloromethane, followed by addition of water.
  • the reaction is carried out preferably at a temperature of from -20 0 C to +100 0 C, more preferably from 20 0 C to 80 0 C, in particular at 50 0 C.
  • a catalyst such as copper(I) oxide
  • the reaction is carried out preferably at a temperature of from -20 0 C to +200 0 C, more preferably from 50 0 C to 150 0 C, in particular at 110 0 C.
  • Vinyl compounds of formula (VIA) are known from the literature (for example, from J. Org. Chem. (2003), 68(15), 5925-5929) or can be made by methods known to a person skilled in the art.
  • a compound of formula (XIV) where A 1 , A 2 , A 3 , A 4 are as defined for a compound of formula (I), R is Ci-C ⁇ alkoxy, R 1 ', R 2 ' and R 3 ' represent optionally substituted alkyl or optionally substituted phenyl and G is oxygen, can be made by reacting a carboxylic acid of formula (XV) where A 1 , A 2 , A 3 , A 4 are as defined for a compound of formula (I) and R is Ci-C ⁇ alkoxy, with an amine (XVI) where R 1 ', R 2 ' and R 3 ' represent optionally substituted alkyl or optionally substituted phenyl.
  • Such reactions are usually carried out in the presence of a coupling reagent, such as N,N'-dicyclohexylcarbodiimide (“DCC”), l-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (“EDC”) or bis(2- oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”), in the presence of a base, and optionally in the presence of a nucleophilic catalyst.
  • DCC N,N'-dicyclohexylcarbodiimide
  • EDC l-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride
  • BOP-Cl bis(2- oxo-3-oxazolidinyl)phosphonic chloride
  • Such reactions are carried out preferably at a temperature of from -20 0 C to +200 0 C, more preferably from 50 0 C to 150
  • Suitable nucleophilic catalysts include hydroxybenzotriazole ("HOBT”).
  • Suitable solvents include dimethylacetamide, tetrahydrofuran, dioxane, 1,2- dimethoxyethane, ethyl acetate and toluene.
  • Amines of formula (XVI) and carboxylic acids of formula (XV) are known from the literature or can be made by methods known to a person skilled in the art.
  • a compound of formula (XIII) where A 1 , A 2 , A 3 , A 4 are as defined for a compound of formula (I) R is Ci-C ⁇ alkoxy, R 1 ', R 2 'and R 3 ' represent optionally substituted alkyl or optionally substituted phenyl and G is oxygen can be made by reacting a compound of formula (XIV) where A 1 , A 2 , A 3 , A 4 are as defined for a compound of formula (I) R is Ci-C ⁇ alkoxy, R 1 ', R 2 ' and R 3 ' represent optionally substituted alkyl or optionally substituted phenyl and G is oxygen , with a thio-transfer reagent, such as Lawesson's reagent or phosphorus pentasulf ⁇ de in a solvent, for example an aromatic solvent, such as toluene.
  • a thio-transfer reagent such as Lawesson's reagent or phosphorus pent
  • a compound of formula (XII) where A 1 , A 2 , A 3 , A 4 are as defined for a compound of formula (I) R is Ci-C ⁇ alkoxy, R 1 ', R 2 'and R 3 ' represent optionally substituted alkyl or optionally substituted phenyl, R 4 ' represents optionally substituted alkyl and G is oxygen can be made by reacting a compound of formula (XIII) where A 1 , A 2 , A 3 , A 4 are as defined for a compound of formula (I) R is Ci-C ⁇ alkoxy, R 1 ', R 2 'and R 3 ' represent optionally substituted alkyl or optionally substituted phenyl and G is oxygen with an alkylating agent R 4 ' -X where X is a leaving group for example
  • a compound of formula (XI) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I), G is oxygen and R is Ci-C ⁇ alkoxy can be made by reacting a compound of formula (XII) where A 1 , A 2 , A 3 , A 4 are as defined for a compound of formula (I) R is Ci-C ⁇ alkoxy, R 1 ', R 2 'and R 3 ' represent optionally substituted alkyl or optionally substituted phenyl, R 4 ' represents optionally substituted alkyl and G is oxygen with a vinyl compound of formula (VI) where R 3 and R 4 are as defined for a compound of formula (I), in the presence of a fluorine reagent such as potassium
  • the reaction is carried out preferably at a temperature of from -20 0 C to +500 0 C, more preferably from 0 0 C to 100 0 C, in particular at ambient temperature.
  • Vinyl compounds of formula (VI) are known from the literature (for example, from EP 1 ,731 ,512) or can be made by methods known to a person skilled in the art.
  • a compound of formula (I) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I) and G is oxygen can be made by reacting a carboxylic acid of formula (III) or an acid halide of formula (IH') where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I), G is oxygen and R is Br, Cl or F (which can be obtained from a compound of the formula (XI) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I), G is oxygen and R is Ci-C ⁇ alkoxy), with an amine of formula HNR 1 R 2 where R 1 and R 2 are as defined for a compound of formula (I) under conditions described under 8).
  • a compound of formula (III) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I) and G is Oxygen can be made by treatment of a compound of formula (XIA) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I) and R is Ci-C ⁇ alkoxy under hydrolytic conditions followed by decarboxylation.
  • Such conditions are, for example, treatment with an alkali hydroxide, such as sodium hydroxide or potassium hydroxide, in a solvent, such as ethanol or tetrahydrofuran, in the presence of water.
  • Another alternative is the treatment of the ester with an acid, such as trifluoroacetic acid, in a solvent, such as dichloromethane, followed by addition of water.
  • the reaction is carried out preferably at a temperature of from -20 0 C to +100 0 C, more preferably from 20 0 C to 80 0 C, in particular at 50 0 C.
  • a compound of formula (XIA) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I) and R is Ci-C ⁇ alkoxy can be made reacting a compound of formula (XII) where A 1 , A 2 , A 3 , A 4 are as defined for a compound of formula (I) R is C 1 - C ⁇ alkoxy, R 1 ', R 2 'and R 3 ' represent optionally substituted alkyl or optionally substituted phenyl, R 4 ' represents optionally substituted alkyl and G is oxygen with a vinyl compound of formula (VIA) where R 3 and R 4 are as defined for a compound of formula (I) and R is Ci-
  • Carboxylic acids of formula (XVIII) where A 1 , A 2 , A 3 , A 4 are as defined for a compound of formula (I), R 1 ', R 2 'and R 3 ' represent optionally substituted alkyl or optionally substituted phenyl, R 4 ' represents optionally substituted alkyl and G is oxygen may be formed from esters of formula (XII), wherein R is Ci-C ⁇ alkoxy. It is known to a person skilled in the art that there are many methods for the hydrolysis of such esters depending on the nature of the alkoxy group.
  • One widely used method to achieve such a transformation is the treatment of the ester with an alkali hydroxide, such as sodium hydroxide or lithium hydroxide, in a solvent, such as ethanol or tetrahydrofuran, in the presence of water.
  • an alkali hydroxide such as sodium hydroxide or lithium hydroxide
  • a solvent such as ethanol or tetrahydrofuran
  • the reaction is carried out at temperatures of from 0 0 C to 150 0 C, preferably from 15°C to 100 0 C, in particular at 50 0 C.
  • a compound of formula (XVII) where A 1 , A 2 , A 3 , A 4 are as defined for a compound of formula (I), R 1 ', R 2 'and R 3 ' represent optionally substituted alkyl or optionally substituted phenyl, R 4 ' represents optionally substituted alkyl and G is oxygen may be formed by reaction of acids of formula (XVIII) where A 1 , A 2 , A 3 , A 4 are as defined for a compound of formula (I), R 1 ', R 2 'and R 3 ' represent optionally substituted alkyl or optionally substituted phenyl, R 4 ' represents optionally substituted alkyl and G is oxygen with an amine of formula HNR 1 R 2 where R 1 and R 2 are as defined for a compound of formula (I) under conditions described under 8).
  • a compound of formula (I) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I) and G is oxygen can be made by reacting a compound of the formula (XVII) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I), G is oxygen, R 1 ', R 2 'and R 3 ' represent optionally substituted alkyl or optionally substituted phenyl and R 4 ' represents optionally substituted alkyl with a vinyl compound of formula (VI) where R 3 and R 4 are as defined for a compound of formula (I), in the presence of a fluorine reagent such as potassium fluoride or tetrabutylammonium fluoride, in a solvent, for example THF under conditions described under 13).
  • a fluorine reagent such as potassium fluoride or
  • a compound of formula (I) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined herein and G is oxygen can be made by treatment of a compound of formula (IA) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I), G is oxygen, and R is Ci-C ⁇ alkoxy, under hydrolytic conditions followed by decarboxylation.
  • Such conditions are, for example, treatment with an alkali hydroxide, such as sodium hydroxide or potassium hydroxide, in a solvent, such as ethanol or tetrahydrofuran, in the presence of water.
  • Another alternative is the treatment of the ester with an acid, such as trifluoroacetic acid, in a solvent, such as dichloromethane, followed by addition of water.
  • the reaction is carried out preferably at a temperature of from -20 0 C to +100 0 C, more preferably from 20 0 C to 80 0 C, in particular at 50 0 C.
  • a compound of formula (IA) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I), G is oxygen, and R is Ci-C ⁇ alkoxy, can be made reacting a compound of formula (XVII) where A 1 , A 2 , A 3 , A 4 are as defined for a compound of formula (I), R 1 ', R 2 'and R 3 ' represent optionally substituted alkyl or optionally substituted phenyl, R 4 ' represents optionally substituted alkyl and G is oxygen with a vinyl compound of formula (VIA) where R 3 and R 4 are as defined for a compound of formula (I) and R is Ci- C ⁇ alkoxy , in the presence of a fluorine reagent such as potassium fluoride or tetrabutylammonium fluoride, in a solvent, for example THF.
  • a fluorine reagent such as potassium fluoride or tetrabuty
  • the reaction is carried out preferably at a temperature of from -20 0 C to +500 0 C, more preferably from 0 0 C to 100 0 C, in particular at ambient temperature.
  • Vinyl compounds of formula (VIA) are known from the literature (for example, from J. Org. Chem. (2003), 68(15), 5925-5929) or can be made by methods known to a person skilled in the art.
  • a compound of formula (I) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined herein and G is oxygen can be made by reacting a compound of the formula (XX) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I) and G is oxygen, with a reducing agent such as Zn/HCl, in a solvent, for example water or DMF or mixtures thereof.
  • the reaction is carried out preferably at a temperature of from -20 0 C to +500 0 C, more preferably from 0 0 C to 100 0 C, in particular at 80 0 C.
  • a compound of formula (XX) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I) and G is oxygen can be made by reacting a compound of the formula (XXI) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I) and G is oxygen (which may be prepared according to the methods described in WO 2009/080250) with nitromethane in the presence of a base such as NaOH, in a solvent, for example water or DMF or mixtures thereof.
  • a base such as NaOH
  • reaction is carried out preferably at a temperature of from -20 0 C to +500 0 C, more preferably from 0 0 C to 100 0 C, in particular at ambient temperature.
  • a compound of formula (I) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined herein and G is oxygen as shown in Scheme 4 can be prepared from a compound of the formula (XX) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I) and G is oxygen via an intermediate (XIX) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I) and G is oxygen, for example under reaction conditions described under 18).
  • a compound of formula (III) where A 1 , A ⁇ 2 , A , A , R a mecanicivitynd, ⁇ T R-j 4 are as defined for a compound of formula (I), G is oxygen can be made from an compound of the formula (XI) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I), G is oxygen and R is Ci-C ⁇ alkoxy under conditions described under 6)
  • a compound of formula (XI) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I), G is oxygen and R is Ci-C ⁇ alkoxy can be made by reacting a compound of formula (XXII) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen as described under 5).
  • a compound of formula (XXII) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen, can be made by reacting a compound of the formula
  • compounds of formula (XXII) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen, as shown in Scheme 5 can be prepared from a compound of the formula (XXIV) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen via an intermediate (XIII) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen for example under reaction conditions described under 18).
  • a compound of formula (XXIV) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen, can be made by reacting a compound of the formula
  • a compound of formula (I) where R are as defined for a compound of formula (I) and G is oxygen can be made by reacting a compound of the formula (XXVI) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I) and G is oxygen, with a reducing agent such as Raney Ni /H 2 , in a solvent, for example methanol or ethanol.
  • the reaction is carried out preferably at a temperature of from -20 0 C to +500 0 C, more preferably from 0 0 C to 100 0 C. Representative experimental conditions for this transformation are described by Allen, C.F.H. and Wilson, CV. in Org Synth. (1947), 27.
  • a compound of formula (XXVI) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I) and G is oxygen can be made by reacting a compound of the formula (XXI) where A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 and R 4 are as defined for a compound of formula (I) and G is oxygen (which may be prepared according to the methods described in WO 2009/080250) with a cyanide source such as sodium cyanide, potassium cyanide, trimethylsilyl cyanide, acetone cyanohydrin, or diethylaluminium cyanide, in a solvent, for example toluene, tetrahydrofuran, acetone, acetic acid, ethanol, or water or mixtures thereof.
  • a cyanide source such as sodium cyanide, potassium cyanide, trimethylsilyl cyan
  • the reaction is carried out preferably at a temperature of from -20 0 C to +500 0 C, more preferably from 0 0 C to 100 0 C, in particular at ambient temperature.
  • Representative experimental conditions for this transformation are described in Tetrahedron, 64(17), 3642-3654; 2008.
  • a compound of formula (XXII) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen, can be made by reacting a compound of the formula (XXVII) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen (which may be prepared according to the methods described in WO 2009/080250) under conditions as described under 26).
  • a compound of formula (XXVII) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen, can be made by reacting a compound of the formula (XXV) where A 1 , A 2 , A 3 , A 4 , R 3 and R 4 are as defined for a compound of formula (I) and X A is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen under conditions as described under 27).
  • Enantiomerically enriched mixtures of compounds of formula (I*) or (I**) may be prepared, for example, according to schemes 4 or 5 by formation of intermediate XX or XXIV via an asymmetric Michael addition, see for example J. Org. Chem. 2008, 73, 3475-3480 and references cited therein".
  • Such enantiomerically enriched mixtures may be prepared according to schemes 6 or 7 by stereoselective addition of cyanide, see for example J. Am. Chem. Soc. 2008, 130, 6072-6073.
  • a compound of formula (I) may be a mixture of compounds I* and I** in any ratio e.g. in a molar ratio of 1 :99 to 99:1, e.g. 10:1 to 1 :10, e.g. a substantially 50:50 molar ratio.
  • the molar proportion of compound I** compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%.
  • the molar proportion of the compound of formula I* compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%.
  • the compounds of formula (I) can be used to control infestations of insect pests such as Lepidoptera, Diptera, Hemiptera, Thysanoptera, Orthoptera, Dictyoptera, Coleoptera, Siphonaptera, Hymenoptera and Isoptera and also other invertebrate pests, for example, acarine, nematode and mollusc pests. Insects, acarines, nematodes and molluscs are hereinafter collectively referred to as pests.
  • the pests which may be controlled by the use of the invention compounds include those pests associated with agriculture (which term includes the growing of crops for food and fiber products), horticulture and animal husbandry, companion animals, forestry and the storage of products of vegetable origin (such as fruit, grain and timber); those pests associated with the damage of man-made structures and the transmission of diseases of man and animals; and also nuisance pests (such as flies).
  • the compounds of the invention may be used for example on turf, ornamentals, such as flowers, shrubs, broad-leaved trees or evergreens, for example conifers, as well as for tree injection, pest management and the like.
  • pest species which may be controlled by the compounds of formula (I) include: Myzus persicae (aphid), Aphis gossypii (aphid), Aphis fabae (aphid), Lygus spp.
  • Capsids Dysdercus spp. (capsids), Nilaparvata lugens (planthopper), Nephotettixc incticeps (leafhopper), Nezara spp. (stinkbugs), Euschistus spp. (stinkbugs), Leptocorisa spp. (stinkbugs), Frankliniella occidentalis (thrip), Thrips spp. (thrips), Leptinotarsa decemlineata (Colorado potato beetle), Anthonomus grandis (boll weevil), Aonidiella spp. (scale insects), Trialeurodes spp.
  • the invention therefore provides a method of controlling insects, acarines, nematodes or molluscs which comprises applying an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), or a composition containing a compound of formula (I), to a pest, a locus of pest, preferably a plant, or to a plant susceptible to attack by a pest.
  • the compounds of formula (I) are preferably used against insects or acarines.
  • the compounds of the invention may also be used for controlling insects that are resistant to known insecticides.
  • plant as used herein includes seedlings, bushes and trees.
  • Crops are to be understood as also including those crops which have been rendered tolerant to herbicides or classes of herbicides (e.g. ALS-, GS-, EPSPS-, PPO- and HPPD- inhibitors) by conventional methods of breeding or by genetic engineering.
  • herbicides or classes of herbicides e.g. ALS-, GS-, EPSPS-, PPO- and HPPD- inhibitors
  • An example of a crop that has been rendered tolerant to imidazolinones, e.g. imazamox, by conventional methods of breeding is Clearf ⁇ eld® summer rape (canola).
  • crops that have been rendered tolerant to herbicides by genetic engineering methods include e.g. glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady® and LibertyLink®.
  • Crops are also to be understood as being those which have been rendered resistant to harmful insects by genetic engineering methods, for example Bt maize (resistant to European corn borer), Bt cotton (resistant to cotton boll weevil) and also Bt potatoes (resistant to Colorado beetle).
  • Bt maize are the Bt 176 maize hybrids of NK® (Syngenta Seeds).
  • Examples of transgenic plants comprising one or more genes that code for an insecticidal resistance and express one or more toxins are KnockOut® (maize), Yield Gard® (maize), NuCOTIN33B® (cotton), Bollgard® (cotton), NewLeaf® (potatoes), NatureGard® and Protexcta®.
  • Plant crops or seed material thereof can be both resistant to herbicides and, at the same time, resistant to insect feeding ("stacked" transgenic events).
  • seed can have the ability to express an insecticidal Cry3 protein while at the same time being tolerant to glyphosate.
  • Crops are also to be understood as being those which are obtained by conventional methods of breeding or genetic engineering and contain so-called output traits (e.g. improved storage stability, higher nutritional value and improved flavor).
  • output traits e.g. improved storage stability, higher nutritional value and improved flavor.
  • a compound of formula (I) is usually formulated into a composition which includes, in addition to the compound of formula (I), a suitable inert diluent or carrier and, optionally, a surface active agent (SFA).
  • SFAs are chemicals which are able to modify the properties of an interface (for example, liquid/solid, liquid/air or liquid/liquid interfaces) by lowering the interfacial tension and thereby leading to changes in other properties (for example dispersion, emulsification and wetting).
  • compositions both solid and liquid formulations
  • the composition is generally used for the control of pests such that a compound of formula (I) is applied at a rate of from O.lg to 10kg per hectare, preferably from Ig to 6kg per hectare, more preferably from Ig to lkg per hectare.
  • a compound of formula (I) is used at a rate of O.OOOlg to 1Og (for example 0.00 Ig or 0.05g), preferably 0.005g to 1Og, more preferably 0.005g to 4g, per kilogram of seed.
  • the present invention provides an insecticidal, acaricidal, nematicidal or molluscicidal composition
  • an insecticidal, acaricidal, nematicidal or molluscicidal composition comprising an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I) and for example a suitable carrier or diluent therefor.
  • the composition is preferably an insecticidal or acaricidal composition.
  • compositions can be chosen from a number of formulation types, including dustable powders (DP), soluble powders (SP), water soluble granules (SG), water dispersible granules (WG), wettable powders (WP), granules (GR) (slow or fast release), soluble concentrates (SL), oil miscible liquids (OL), ultra low volume liquids (UL), emulsif ⁇ able concentrates (EC), dispersible concentrates (DC), emulsions (both oil in water (EW) and water in oil (EO)), micro-emulsions (ME), suspension concentrates (SC), aerosols, fogging/smoke formulations, capsule suspensions (CS) and seed treatment formulations.
  • the formulation type chosen in any instance will depend upon the particular purpose envisaged and the physical, chemical and biological properties of the compound of formula (I).
  • Dustable powders may be prepared by mixing a compound of formula (I) with one or more solid diluents (for example natural clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk, diatomaceous earths, calcium phosphates, calcium and magnesium carbonates, sulfur, lime, flours, talc and other organic and inorganic solid carriers) and mechanically grinding the mixture to a fine powder.
  • solid diluents for example natural clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk, diatomaceous earths, calcium phosphates, calcium and magnesium carbonates, sulfur, lime, flours, talc and other organic and inorganic solid carriers
  • Soluble powders may be prepared by mixing a compound of formula (I) with one or more water-soluble inorganic salts (such as sodium bicarbonate, sodium carbonate or magnesium sulfate) or one or more water-soluble organic solids (such as a polysaccharide) and, optionally, one or more wetting agents, one or more dispersing agents or a mixture of said agents to improve water dispersibility/solubility. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water soluble granules (SG).
  • water-soluble inorganic salts such as sodium bicarbonate, sodium carbonate or magnesium sulfate
  • water-soluble organic solids such as a polysaccharide
  • WP Wettable powders
  • WG Water dispersible granules
  • Granules may be formed either by granulating a mixture of a compound of formula (I) and one or more powdered solid diluents or carriers, or from pre-formed blank granules by absorbing a compound of formula (I) (or a solution thereof, in a suitable agent) in a porous granular material (such as pumice, attapulgite clays, fuller's earth, kieselguhr, diatomaceous earths or ground corn cobs) or by adsorbing a compound of formula (I) (or a solution thereof, in a suitable agent) on to a hard core material (such as sands, silicates, mineral carbonates, sulfates or phosphates) and drying if necessary.
  • a hard core material such as sands, silicates, mineral carbonates, sulfates or phosphates
  • Agents which are commonly used to aid absorption or adsorption include solvents (such as aliphatic and aromatic petroleum solvents, alcohols, ethers, ketones and esters) and sticking agents (such as polyvinyl acetates, polyvinyl alcohols, dextrins, sugars and vegetable oils).
  • solvents such as aliphatic and aromatic petroleum solvents, alcohols, ethers, ketones and esters
  • sticking agents such as polyvinyl acetates, polyvinyl alcohols, dextrins, sugars and vegetable oils.
  • One or more other additives may also be included in granules (for example an emulsifying agent, wetting agent or dispersing agent).
  • DC Dispersible Concentrates
  • a compound of formula (I) may be prepared by dissolving a compound of formula (I) in water or an organic solvent, such as a ketone, alcohol or glycol ether. These solutions may contain a surface active agent (for example to improve water dilution or prevent crystallization in a spray tank).
  • Emulsif ⁇ able concentrates (EC) or oil- in- water emulsions (EW) may be prepared by dissolving a compound of formula (I) in an organic solvent (optionally containing one or more wetting agents, one or more emulsifying agents or a mixture of said agents).
  • Suitable organic solvents for use in ECs include aromatic hydrocarbons (such as alkylbenzenes or alkylnaphthalenes, exemplified by SOLVESSO 100, SOLVESSO 150 and SOLVESSO 200; SOLVESSO is a Registered Trade Mark), ketones (such as cyclohexanone or methylcyclohexanone) and alcohols (such as benzyl alcohol, furfuryl alcohol or butanol), JV-alkylpyrrolidones (such as JV-methylpyrrolidone or JV-octylpyrrolidone), dimethyl amides of fatty acids (such as Cs-Cio fatty acid dimethylamide) and chlorinated hydrocarbons.
  • aromatic hydrocarbons such as alkylbenzenes or alkylnaphthalenes, exemplified by SOLVESSO 100, SOLVESSO 150 and SOLVESSO 200; SOLVESSO is a Registered Trade Mark
  • ketones such
  • An EC product may spontaneously emulsify on addition to water, to produce an emulsion with suff ⁇ cient stability to allow spray application through appropriate equipment.
  • Preparation of an EW involves obtaining a compound of formula (I) either as a liquid (if it is not a liquid at room temperature, it may be melted at a reasonable temperature, typically below 70 0 C) or in solution (by dissolving it in an appropriate solvent) and then emulsifiying the resultant liquid or solution into water containing one or more SFAs, under high shear, to produce an emulsion.
  • Suitable solvents for use in EWs include vegetable oils, chlorinated hydrocarbons (such as chlorobenzenes), aromatic solvents (such as alkylbenzenes or alkylnaphthalenes) and other appropriate organic solvents which have a low solubility in water.
  • Microemulsions may be prepared by mixing water with a blend of one or more solvents with one or more SFAs, to produce spontaneously a thermodynamically stable isotropic liquid formulation.
  • a compound of formula (I) is present initially in either the water or the solvent/SFA blend.
  • Suitable solvents for use in MEs include those hereinbefore described for use in ECs or in EWs.
  • An ME may be either an oil-in-water or a water-in-oil system (which system is present may be determined by conductivity measurements) and may be suitable for mixing water-soluble and oil- soluble pesticides in the same formulation.
  • An ME is suitable for dilution into water, either remaining as a microemulsion or forming a conventional oil-in-water emulsion.
  • SC Suspension concentrates
  • SCs may comprise aqueous or non-aqueous suspensions of finely divided insoluble solid particles of a compound of formula (I).
  • SCs may be prepared by ball or bead milling the solid compound of formula (I) in a suitable medium, optionally with one or more dispersing agents, to produce a fine particle suspension of the compound.
  • One or more wetting agents may be included in the composition and a suspending agent may be included to reduce the rate at which the particles settle.
  • a compound of formula (I) may be dry milled and added to water, containing agents hereinbefore described, to produce the desired end product.
  • Aerosol formulations comprise a compound of formula (I) and a suitable propellant (for example /? -butane).
  • a compound of formula (I) may also be dissolved or dispersed in a suitable medium (for example water or a water miscible liquid, such as n-propanol) to provide compositions for use in non-pressurized, hand-actuated spray pumps.
  • a compound of formula (I) may be mixed in the dry state with a pyrotechnic mixture to form a composition suitable for generating, in an enclosed space, a smoke containing the compound.
  • Capsule suspensions may be prepared in a manner similar to the preparation of EW formulations but with an additional polymerization stage such that an aqueous dispersion of oil droplets is obtained, in which each oil droplet is encapsulated by a polymeric shell and contains a compound of formula (I) and, optionally, a carrier or diluent therefor.
  • the polymeric shell may be produced by either an interfacial poly condensation reaction or by a coacervation procedure.
  • the compositions may provide for controlled release of the compound of formula (I) and they may be used for seed treatment.
  • a compound of formula (I) may also be formulated in a biodegradable polymeric matrix to provide a slow, controlled release of the compound.
  • a composition may include one or more additives to improve the biological performance of the composition (for example by improving wetting, retention or distribution on surfaces; resistance to rain on treated surfaces; or uptake or mobility of a compound of formula (I)).
  • additives include surface active agents, spray additives based on oils, for example certain mineral oils or natural plant oils (such as soy bean and rape seed oil), and blends of these with other bio-enhancing adjuvants (ingredients which may aid or modify the action of a compound of formula (I)).
  • a compound of formula (I) may also be formulated for use as a seed treatment, for example as a powder composition, including a powder for dry seed treatment (DS), a water soluble powder (SS) or a water dispersible powder for slurry treatment (WS), or as a liquid composition, including a flowable concentrate (FS), a solution (LS) or a capsule suspension (CS).
  • DS powder for dry seed treatment
  • SS water soluble powder
  • WS water dispersible powder for slurry treatment
  • CS capsule suspension
  • the preparations of DS, SS, WS, FS and LS compositions are very similar to those of, respectively, DP, SP, WP, SC and DC compositions described above.
  • Compositions for treating seed may include an agent for assisting the adhesion of the composition to the seed (for example a mineral oil or a film-forming barrier).
  • Wetting agents, dispersing agents and emulsifying agents may be surface SFAs of the cationic, anionic, amphoteric or non-ionic type.
  • Suitable SFAs of the cationic type include quaternary ammonium compounds (for example cetyltrimethyl ammonium bromide), imidazolines and amine salts.
  • Suitable anionic SFAs include alkali metals salts of fatty acids, salts of aliphatic monoesters of sulfuric acid (for example sodium lauryl sulfate), salts of sulfonated aromatic compounds (for example sodium dodecylbenzenesulfonate, calcium dodecylbenzenesulfonate, butylnaphthalene sulfonate and mixtures of sodium di- ⁇ opropyl- and tri- ⁇ opropyl-naphthalene sulfonates), ether sulfates, alcohol ether sulfates (for example sodium laureth-3-sulfate), ether carboxylates (for example sodium laureth-3-carboxylate), phosphate esters (products from the reaction between one or more fatty alcohols and phosphoric acid (predominately mono-esters) or phosphorus pentoxide (predominately di- esters), for example the reaction between lauryl alcohol and te
  • Suitable SFAs of the amphoteric type include betaines, propionates and glycinates.
  • Suitable SFAs of the non- ionic type include condensation products of alkylene oxides, such as ethylene oxide, propylene oxide, butylene oxide or mixtures thereof, with fatty alcohols (such as oleyl alcohol or cetyl alcohol) or with alkylphenols (such as octylphenol, nonylphenol or octylcresol); partial esters derived from long chain fatty acids or hexitol anhydrides; condensation products of said partial esters with ethylene oxide; block polymers (comprising ethylene oxide and propylene oxide); alkanolamides; simple esters (for example fatty acid polyethylene glycol esters); amine oxides (for example lauryl dimethyl amine oxide); and lecithins.
  • Suitable suspending agents include hydrophilic colloids (such as polysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose) and swelling clays (such as bentonite or attapulgite).
  • hydrophilic colloids such as polysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose
  • swelling clays such as bentonite or attapulgite
  • a compound of formula (I) may be applied by any of the known means of applying pesticidal compounds. For example, it may be applied, formulated or unformulated, to the pests or to a locus of the pests (such as a habitat of the pests, or a growing plant liable to infestation by the pests) or to any part of the plant, including the foliage, stems, branches or roots, to the seed before it is planted or to other media in which plants are growing or are to be planted (such as soil surrounding the roots, the soil generally, paddy water or hydroponic culture systems), directly or it may be sprayed on, dusted on, applied by dipping, applied as a cream or paste formulation, applied as a vapor or applied through distribution or incorporation of a composition (such as a granular composition or a composition packed in a water-soluble bag) in soil or an aqueous environment.
  • a locus of the pests such as a habitat of the pests, or a growing plant liable to infestation by the pests
  • a compound of formula (I) may also be injected into plants or sprayed onto vegetation using electrodynamic spraying techniques or other low volume methods, or applied by land or aerial irrigation systems.
  • compositions for use as aqueous preparations are generally supplied in the form of a concentrate containing a high proportion of the active ingredient, the concentrate being added to water before use.
  • These concentrates which may include DCs, SCs, ECs, EWs, MEs, SGs, SPs, WPs, WGs and CSs, are often required to withstand storage for prolonged periods and, after such storage, to be capable of addition to water to form aqueous preparations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment.
  • Such aqueous preparations may contain varying amounts of a compound of formula (I) (for example 0.0001 to 10%, by weight) depending upon the purpose for which they are to be used.
  • a compound of formula (I) may be used in mixtures with fertilizers (for example nitrogen-, potassium- or phosphorus-containing fertilizers). Suitable formulation types include granules of fertilizer. The mixtures preferably contain up to 25% by weight of the compound of formula (I).
  • fertilizers for example nitrogen-, potassium- or phosphorus-containing fertilizers.
  • Suitable formulation types include granules of fertilizer.
  • the mixtures preferably contain up to 25% by weight of the compound of formula (I).
  • the invention therefore also provides a fertilizer composition
  • a fertilizer composition comprising a fertilizer and a compound of formula (I).
  • the compositions of this invention may contain other compounds having biological activity, for example micronutrients or compounds having fungicidal activity or which possess plant growth regulating, herbicidal, insecticidal, nematicidal or acaricidal activity.
  • the compound of formula (I) may be the sole active ingredient of the composition or it may be admixed with one or more additional active ingredients such as a pesticide, fungicide, synergist, herbicide or plant growth regulator where appropriate.
  • An additional active ingredient may: provide a composition having a broader spectrum of activity or increased persistence at a locus; synergize the activity or complement the activity (for example by increasing the speed of effect or overcoming repellency) of the compound of formula (I); or help to overcome or prevent the development of resistance to individual components.
  • the particular additional active ingredient will depend upon the intended utility of the composition.
  • Suitable pesticides include the following: a) Pyrethroids, such as permethrin, cypermethrin, fenvalerate, esfenvalerate, deltamethrin, cyhalothrin (in particular lambda-cyhalothrin, gamma-cyhalothrin), bifenthrin, fenpropathrin, cyfluthrin, tefluthrin, fish safe pyrethroids (for example ethofenprox), natural pyrethrin, tetramethrin, S-bioallethrin, fenfluthrin, prallethrin or 5-benzyl-3-furylmethyl-(E)-(lR,3S)-2,2-dimethyl- 3 -(2-oxothio lan-3 -ylidenemethyl)cyclopropane carboxylate; b) Organophosphates, such as profenof
  • pesticides having particular targets may be employed in the composition, if appropriate for the intended utility of the composition.
  • selective insecticides for particular crops for example stemborer specific insecticides (such as cartap) or hopper specific insecticides (such as buprofezin) for use in rice may be employed.
  • insecticides or acaricides specific for particular insect species/stages may also be included in the compositions (for example acaricidal ovo-larvicides, such as clofentezine, flubenzimine, hexythiazox or tetradifon; acaricidal motilicides, such as dicofol or propargite; acaricides, such as bromopropylate or chlorobenzilate; or growth regulators, such as hydramethylnon, cyromazine, methoprene, chlorfluazuron or diflubenzuron).
  • acaricidal ovo-larvicides such as clofentezine, flubenzimine, hexythiazox or tetradifon
  • acaricidal motilicides such as dicofol or propargite
  • acaricides such as bromopropylate or chlorobenzilate
  • growth regulators such
  • fungicidal compounds which may be included in the composition of the invention are (E)- ⁇ /-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy- iminoacetamide (SSF- 129), 4-bromo-2-cyano-N, ⁇ /-dimethyl-6-trifluoromethyl- benzimidazole- 1 -sulfonamide, ⁇ -[ ⁇ /-(3-chloro-2,6-xylyl)-2-methoxyacetamido]- ⁇ -butyro lactone, 4-chloro-2-cyano- ⁇ /, ⁇ /-dimethyl-5-/?-tolylimidazole- 1 -sulfonamide (IKF-916, cyamidazosulfamid), 3-5-dichloro-iV-(3-chloro- 1 -ethyl- 1 -methyl-2-oxopropyl)-4- methylbenzamide (R)
  • acibenzolar-S-methyl alanycarb, aldimorph, anilazine, azaconazole, azoxystrobin, benalaxyl, benomyl, benthiavalicarb, biloxazol, bitertanol, bixafen, blasticidin S, boscalid, bromuconazole, bupirimate, captafol, captan, carbendazim, carbendazim chlorhydrate, carboxin, carpropamid, carvone, CGA41396, CGA41397, chinomethionate, chlorothalonil, chlorozolinate, clozylacon, copper containing compounds such as copper oxychloride, copper oxyquinolate, copper sulfate, copper tallate and Bordeaux mixture, cyclufenamid, cymoxanil, cyproconazole, cyprodinil, debacarb, di-2-pyridyl disulfide
  • the compounds of formula (I) may be mixed with soil, peat or other rooting media for the protection of plants against seed-borne, soil-borne or foliar fungal diseases.
  • synergists for use in the compositions include piperonyl butoxide, sesamex, safroxan and dodecyl imidazole.
  • Suitable herbicides and plant-growth regulators for inclusion in the compositions will depend upon the intended target and the effect required.
  • a rice selective herbicide which may be included is propanil.
  • An example of a plant growth regulator for use in cotton is PIXTM.
  • Some mixtures may comprise active ingredients which have significantly different physical, chemical or biological properties such that they do not easily lend themselves to the same conventional formulation type. In these circumstances other formulation types may be prepared. For example, where one active ingredient is a water insoluble solid and the other a water insoluble liquid, it may nevertheless be possible to disperse each active ingredient in the same continuous aqueous phase by dispersing the solid active ingredient as a suspension
  • the resultant composition is a suspoemulsion (SE) formulation.
  • MS ZQ Mass Spectrometer from Waters single quadrupole mass spectrometer
  • ionization method electrospray, polarity: positive ionization, capillary (kV) 3.00, cone (V) 30.00, source temperature ( 0 C) 100, desolvation temperature ( 0 C) 250, cone gas flow (L/Hr) 50, desolvation gas flow (L/Hr) 400, mass range: 150 to IQOO Da.
  • LC HP 1100 HPLC from Agilent solvent degasser, quaternary pump, heated column compartment and diode-array detector.
  • MS ZMD Mass Spectrometer from Waters single quadrupole mass spectrometer
  • ionization method electrospray, polarity: positive ionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V) 3.00, source temperature ( 0 C) 150, desolvation temperature ( 0 C) 320, cone gas flow (L/Hr) 50, desolvation gas flow (L/Hr) 400, mass range: 150 to 800 Da.
  • MS ZQ Mass Spectrometer from Waters single quadrupole mass spectrometer
  • ionization method electrospray, polarity: positive ionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V) 3.00, source temperature ( 0 C) 100, desolvation temperature ( 0 C) 200, cone gas flow (L/Hr) 200, desolvation gas flow (L/Hr) 250, mass range: 150 to 800 Da.
  • LC 1 lOOer Series HPLC from Agilent quaternary pump, heated column compartment and diode-array detector.
  • MS ZMD Mass Spectrometer from Waters single quadrupole mass spectrometer
  • ionization method electrospray, polarity: positive ionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V) 3.00, source temperature ( 0 C) 150, desolvation temperature ( 0 C) 320, cone gas flow (L/Hr) 50, desolvation gas flow (L/Hr) 400, mass range: 150 to 800 Da.
  • MS ZQ Mass Spectrometer from Waters single quadrupole mass spectrometer
  • ionization method electrospray, polarity: positive ionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V) 3.00, source temperature ( 0 C) 100, desolvation temperature ( 0 C) 200, cone gas flow (L/Hr) 200, desolvation gas flow (L/Hr) 250, mass range: 150 to 800 Da.
  • the reaction mixture was stirred in a pressure reactor in an atmosphere of carbon monoxide (6 bar) at 85°C for 16 hours.
  • the reaction mixture was cooled to ambient temperature, the ethanol was evaporated and aqueous sodium hydrogen carbonate (saturated) (200 ml) and ethyl acetate (250 ml) were added.
  • the phases were separated and the organic phase was dried over sodium sulfate and concentrated.
  • Cataxium A (68 mg) and palladium acetate (13 mg) were dissolved in butanol (30 ml) under an argon atmosphere.
  • Tetramethylene diamine (0.29 ml) and 5-(4-bromo-3-chloro-phenyl)-3- (3,5-dichloro-phenyl)-3-methyl-3,4-dihydro-2H-pyrrole (1.11 g) were added at ambient temperature.
  • the reaction mixture was stirred in a pressure reactor in an atmosphere of carbon monoxide (6 bar) at 115°C for 16 hours.
  • the reaction mixture was cooled to ambient temperature, filtered and ethyl acetate (250 ml) was added.
  • Example Pl Method for preparing the compounds of the invention from a carboxylic acid
  • Table A provides compounds of formula (Ia) where G is oxygen, R 3 is trifluoromethyl, R 4 is
  • R 5 is methyl
  • R 1 and R 2 have the values listed in the table below.
  • Table B provides compounds of formula (Ia) where G is oxygen, R 1 is Hydrogen, R 5 is methyl, R 3 is trifluoromethyl, and R 2 and R 4 have the values listed in the table below.
  • Table C provides compounds of formula (Ia) where G is oxygen, R 1 is Hydrogen, R 4 is 3,5- dichloro -phenyl-, and R 2 , R 3 and R 5 have the values listed in the table below.
  • Table D provides compounds of formula (Ib) where G is oxygen, R 3 is trifluoromethyl, R 4 is
  • Cotton leaf discs were placed on agar in a 24-well microtiter plate and sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs were infested with 5 Ll larvae. The samples were checked for mortality, feeding behavior, and growth regulation 3 days after treatment (DAT). The following compound gave at least 80% control of Spodoptera littoralis: Al, A2, A3, A4, A5, A6, A7, A8, A9, AlO, Bl, B2, B3, B4, B5, B6, Cl, C2, C3, Dl, D2, D3
  • MTP microtiter plate
  • Diabrotica balteata (Corn root worm): A 24-well microtiter plate (MTP) with artificial diet was treated with test solutions at an application rate of 200 ppm (concentration in well 18 ppm) by pipetting. After drying, the
  • MTP's were infested with L2 larvae (6-10 per well). After an incubation period of 5 days, samples were checked for larval mortality and growth regulation.
  • Diabrotica balteata Al, A2, A3, A4 , A5, A6, A7, A8, A9, AlO, Bl, B2, B3, B4, B5, B6, Cl, C2, C3, Dl, D2, D3.
  • Thrips tabaci Onion thrips
  • Sunflower leaf discs were placed on agar in a 24-well microtiter plate and sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs were infested with an aphid population of mixed ages. After an incubation period of 7 days, samples were checked for mortality.
  • Thrips tabaci Al, A2, A3, A4, A5, A6, A7, A8, A9, AlO, Bl, B2, B3, B4, B5, B6, Cl, C2, C3, Dl, D2, D3.
  • Tetranychus urticae (Two-spotted spider mite):
  • Bean leaf discs on agar in 24-well microtiter plates were sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs are infested with mite populations of mixed ages. 8 days later, discs are checked for egg mortality, larval mortality, and adult mortality. The following compound gave at least 80% control of Tetranychus urticae: Al, A2, A3, A4 ,A5, A6, A7, A8, A9, AlO, Bl, B2, B3, B4, B5, B6, Cl, C2, C3, Dl, D2, D3.

Abstract

The invention relates to compounds of formula (I) where A1, A2, A3, A4, G, R1, R2, R3 and R4 are as defined in claim 1; or a salt or JV-oxide thereof. Furthermore, the present invention relates to processes and intermediates for preparing compounds of formula (I), to insecticidal, acaricidal, nematicidal and molluscicidal compositions comprising the compounds of formula (I) and to methods of using the compounds of formula (I) to control insect, acarine, nematode and mollusc pests.

Description

INSECTICIDAL COMPOUNDS
The present invention relates to certain dihydro -pyrrole derivatives with a four- membered ring as terminal group, to processes and intermediates for preparing these derivatives, to insecticidal, acaricidal, nematicidal and molluscicidal compositions comprising these derivatives and to methods of using these derivatives to control insect, acarine, nematode and mollusc pests.
Certain dihydro-pyrrole derivatives with insecticidal properties are disclosed in, for example, JP 2007/091708 and JP 2008/133273. It has now surprisingly been found that dihydro-pyrrole derivatives with a four- membered ring as terminal group have insecticidal properties.
The present invention therefore provides a compound of formula (I)
where A1, A2, A3 and A4 are independently of each other C-H, C-R5 or nitrogen; G is oxygen or sulfur;
R1 is hydrogen, Ci-Csalkyl, Ci-Csalkoxy-, Ci-Csalkylcarbonyl- or Ci-Csalkoxycarbonyl-; R2 is a group of formula (II)
Y^γ2
*Λr (H)
RB where
L is a single bond or Ci-Cβalkylene; and
Y1, Y2 and Y3 are independently of another CR8R9, C=O, C=N-OR10, N-R10, S, SO, SO2, S=N-R10 or SO=N-R10, provided that at least one of Y1, Y2 or Y3 is not CR8R9, C=O or C=N- OR10; R3 is Ci-Cshaloalkyl;
R4 is aryl or aryl substituted by one to five R7, or heteroaryl or heteroaryl substituted by one to five R7; each R5 is independently halogen, cyano, nitro, Ci-Csalkyl, Ci-Cshaloalkyl, Ci-Csalkenyl, Ci-Cshaloalkenyl, Ci-Csalkynyl, Ci-Cshaloalkynyl, C3-Ciocycloalkyl, Ci-Csalkoxy-, Ci- C8haloalkoxy-, Ci-C8alkylthio-, Ci-Cghaloalkylthio-, Ci-C8alkylsulfmyl-, Ci-C8haloalkyl- sulfϊnyl-, Ci-Csalkylsulfonyl- or Ci-Cshaloalkylsulfonyl-, or two R5 on adjacent carbon atoms together form a -CH=CH-CH=CH- bridge; R6 is hydrogen or Ci-Csalkyl; each R7 is independently halogen, cyano, nitro, Ci-Csalkyl, Ci-Cshaloalkyl, C2-C8alkenyl, C2-C8haloalkenyl, C2-C8alkynyl, C2-Cshaloalkynyl, hydroxy, Ci-Csalkoxy-, C1- Cshaloalkoxy-, mercapto, Ci-Csalkylthio-, Ci-Cshaloalkylthio-, Ci-Csalkylsulfϊnyl-, Ci- Cshaloalkylsulfinyl-, Ci-Csalkylsulfonyl-, Ci-Cshaloalkylsulfonyl-, Ci-Csalkylcarbonyl-, Ci- Csalkoxycarbonyl-, aryl or aryl substituted by one to five R11, or heterocyclyl or heterocyclyl substituted by one to five R1 ! ; each R8 and R9 is independently hydrogen, halogen, Ci-Csalkyl or Ci-Cshaloalkyl; each R10 is independently hydrogen, cyano, Ci-Csalkyl, Ci-Cshaloalkyl, Ci-Csalkylcarbonyl- , Ci-Cshaloalkylcarbonyl-, Ci-Csalkoxycarbonyl-, Ci-Cshaloalkoxycarbonyl-, Ci-Csalkyl- sulfonyl-, Ci-Cshaloalkylsulfonyl-, aryl-Ci-C4alkylene- or aryl-Ci-C4alkylene- where the aryl moiety is substituted by one to three R12, or or heteroaryl-Ci- C4alkylene- where the heteroaryl moiety is substituted by one to three R12; each R11 and R12 is independently halogen, cyano, nitro, d-Cgalkyl, d-Cghaloalkyl, C1- Csalkoxy-, Ci-Cshaloalkoxy- or Ci-Csalkoxycarbonyl-; or a salt or JV-oxide thereof. The compounds of formula (I) may exist in different geometric or optical isomers or tautomeric forms. This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.
The compounds of the invention may contain one or more asymmetric carbon atoms, for example, at the -CR3R4- group, and may exist as enantiomers (or as pairs of diastereo- isomers) or as mixtures of such.
Alkyl groups (either alone or as part of a larger group, such as alkoxy-, alkylthio-, alkylsulfmyl-, alkylsulfonyl-, alkylcarbonyl- or alkoxycarbonyl-) can be in the form of a straight or branched chain and are, for example, methyl, ethyl, propyl, prop-2-yl, butyl, but- 2-yl, 2-methyl-prop-l-yl or 2-methyl-prop-2-yl. The alkyl groups are, unless indicated to the contrary, preferably Ci-C6, more preferably C1-C4, most preferably C1-C3 alkyl groups. Alkylene groups can be in the form of a straight or branched chain and are, for example, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, or -CH(CH2CH3)-. The alkylene groups are, unless indicated to the contrary, preferably Ci-C3, more preferably Ci-C2, most preferably Ci alkylene groups. Alkenyl groups can be in the form of straight or branched chains, and can be, where appropriate, of either the (E)- or (Z)-confϊguration. Examples are vinyl and allyl. The alkenyl groups are, unless indicated to the contrary, preferably C2-C6, more preferably C2-C4, most preferably C2-C3 alkenyl groups. Alkynyl groups can be in the form of straight or branched chains. Examples are ethynyl and propargyl. The alkynyl groups are, unless indicated to the contrary, preferably C2-C6, more preferably C2-C4, most preferably C2-C3 alkynyl groups.
Halogen is fluorine, chlorine, bromine or iodine.
Haloalkyl groups (either alone or as part of a larger group, such as haloalkoxy-, halo alky It hio-, haloalkylsulfmyl-, haloalkylsulfonyl-, halo alky lcarbonyl- or haloalkoxycarbonyl-) are alkyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, difluoromethyl, trifluoromethyl, chlorodifluoromethyl or 2,2,2-trifluoro-ethyl.
Haloalkenyl groups are alkenyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, 2,2-difluoro-vinyl or l,2-dichloro-2- fluoro-vinyl.
Haloalkynyl groups are alkynyl groups which are substituted by one or more of the same or different halogen atoms and are, for example, l-chloro-prop-2-ynyl.
Cycloalkyl groups can be in mono- or bi-cyclic form and are, for example, cyclopropyl, cyclobutyl, cyclohexyl and bicyclo[2.2.1]heptan-2-yl. The cycloalkyl groups are, unless indicated to the contrary, preferably C3-C8, more preferably C3-C6 cycloalkyl groups.
Aryl groups are aromatic ring systems which can be in mono-, bi- or tricyclic form. Examples of such rings include phenyl, naphthyl, anthracenyl, indenyl or phenanthrenyl. Preferred aryl groups are phenyl and naphthyl, phenyl being most preferred. Where an aryl moiety is said to be substituted, the aryl moiety is, unless indicated to the contrary, preferably substituted by one to four substituents, most preferably by one to three substituents.
Heteroaryl groups are aromatic ring system containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three heteroatoms and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulfur. Examples of monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl. Examples of bicyclic groups include quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl and benzothiazolyl. Monocyclic heteroaryl groups are preferred, pyridyl being most preferred. Where a heteroaryl moiety is said to be substituted, the heteroaryl moiety is, unless indicated to the contrary, preferably substituted by one to four substituents, most preferably by one to three substituents.
Heterocyclyl groups are defined to include heteroaryl groups and in addition their unsaturated or partially unsaturated analogues. Examples of monocyclic groups include thietanyl, pyrrolidinyl, tetrahydrofuranyl, [l,3]dioxolanyl, piperidinyl, piperazinyl, [l,4]dioxanyl, and morpholinyl or their oxidised versions such as 1-oxo -thietanyl and 1,1- dioxo -thietanyl. Examples of bicyclic groups include 2,3-dihydro-benzofuranyl, benzo[l,3]dioxolanyl, and 2,3-dihydro-benzo[l,4]dioxinyl. Where a heterocyclyl moiety is said to be substituted, the heterocyclyl moiety is, unless indicated to the contrary, preferably substituted by one to four substituents, most preferably by one to three substituents.
Preferred values of A1, A2, A3, A4, G, R1, R2, R3, R4, L, Y1, Y2, Y3, R5, R6, R7, R8, R9, R10, R11, R12, R13 and m are, in any combination, as set out below.
Preferably no more than two of A1, A2, A3 and A4 are nitrogen.
Preferably A1 is C-H or C-R5, most preferably A1 is C-R5.
Preferably A2 is C-H or C-R5, most preferably A2 is C-H.
Preferably A3 is C-H or C-R5, most preferably A3 is C-H. Preferably A4 is C-H or C-R5, most preferably A4 is C-H.
In one preferred group of compounds A1, A2, A3 and A4 are independently of each other C-H or C-R5.
In one preferred group of compounds A1 is C-R5, A2 is C-H, A3 is C-H or nitrogen and A4 is C-H or nitrogen. In another preferred group of compounds A1 is C-R5, A2 is C-H, A3 is C-H or nitrogen and A4 is C-H.
In a further preferred group of compounds A1 is C-R5, A2 is C-H, A3 is C-H and A4 is C-H.
Preferably G is oxygen. Preferably R1 is hydrogen, methyl, ethyl, methylcarbonyl- or methoxycarbonyl-, more preferably hydrogen, methyl or ethyl, most preferably hydrogen. Preferably R2 is a group of formula (Ha)
where
L is a single bond, methylene, ethylene or propylene, R13 is Ci-C8alkyl, m is O, 1, 2, 3, 4, or 5, and one of Y1 and Y2 is S, SO, SO2, S=N-R10, SO=N-R10 or C=N-OR10, e.g. S, SO, SO2, S=N- R10 or SO=N-R10, e.g. S, SO, SO2 or C=N-OR10, e.g. S, SO or SO2, and the other is CH2 in which each H may be replaced by R13. More preferably R2 is a group of formula (lib)
where
L is a single bond, methylene, ethylene or propylene, R13 is hydrogen or d-Cgalkyl, e.g. d-Cgalkyl, and one of Y1 and Y2 is S, SO, SO2, S=N-R10, SO=N-R10 or C=N-OR10, e.g. S, SO, SO2, S=N- R10 or SO=N-R10, e.g. S, SO, SO2 or C=N-OR10, e.g. S, SO or SO2, and the other is CH2. More preferably R2 is a group of formula (lie)
where R13 is d-Cgalkyl, preferably methyl, m is O, 1, 2, 3, 4, or 5, and YY22 iiss SS,, SSOO,, SO2, S=N-R10, SO=N-R10 or C=N-OR10, e.g. S, SO, SO2 or C=N-OR10, e.g. S, SO or SO2.
Even more preferably R2 is a group of formula (Hd)
where
R , 13 is hydrogen or Ci-Csalkyl, e.g. Ci-Csalkyl, e.g. hydrogen or methyl, and Y2 is S, SO, SO2, S=N-R10, SO=N-R10 or C=N-OR10, e.g. S, SO, SO2 or C=N-OR10, e.g. S, SO or SO2,
Most preferably R2 is thietan-3-yl-, l-oxo-thietan-3-yl-, l,l-dioxo-thietan-3-yl- or 3- methyl-thietan-3 -yl- .
In another preferred group of compounds R2 is a group of formula (Hc')
where
R13 is Ci-Csalkyl, m is O, 1, 2, 3, 4, or 5, and Y2 is S, SO, SO2, S=N-R10 or SO=N-R10.
In another group of preferred compounds R2 is a group of formula (Hd')
where
R13 is Ci-C8alkyl, and Y2 is S, SO, SO2, S=N-R10 or SO=N-R10.
Preferably R3 is chlorodifluoromethyl or trifluoromethyl, most preferably trifluoro- methyl.
Preferably R4 is phenyl or phenyl substituted by one to five R7, more preferably phenyl substituted by one to three R7, even more preferably R4 is 3,5-dibromo-phenyl-, 3,5- dichloro -phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-, 3,4-dichloro-phenyl-, 3,4,5-trichloro- phenyl- or 3-trifluoromethyl-phenyl-, most preferably 3,5-dichloro-phenyl. Preferably L is a single bond, methylene, ethylene or propylene. More preferably L is methylene or a single bond. Even more preferably L is a single bond. Preferably Y1 is CR8R9, more preferably CH2.
Preferably Y2 is S, SO, SO2, S=N-R10, SO=N-R10, or C=N-OR10, e.g. S, SO, SO2, S=N-R10 or SO=N-R10, more preferably S, SO, SO2, S=N-C≡N, SO=NH, SO=N-C≡N or C=N-OR10 e.g. S, SO, SO2, S=N-C≡N, SO=NH or S0=N-C≡N, most preferably S, SO, SO2 or C=N-OR10, e.g. S, SO or SO2. Preferably Y3 is CR8R9, more preferably CH2. Preferably each R5 is independently halogen, d-Cgalkyl, Ci-Cshaloalkyl or Ci-
Csalkenyl, or two R5 on adjacent carbon atoms together form a -CH=CH-CH=CH- bridge, more preferably each R5 is independently bromo, chloro, fluoro, methyl, trifluoromethyl or vinyl, or two R5 on adjacent carbon atoms, preferably R5 on A1 and A2, together form a - CH=CH-CH=CH- bridge, most preferably each R5 is independently methyl. Preferably R6 is methyl or hydrogen.
Preferably each R7 is independently halogen, cyano, Ci-Csalkyl, Ci-Cshaloalkyl or Ci-Csalkoxy-, more preferably bromo, chloro, fluoro, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy, preferably bromo, chloro or trifluoromethyl, most preferably bromo or chloro.
Preferably each R8 is independently hydrogen or Ci-Csalkyl, more preferably hydrogen or methyl, most preferably hydrogen.
Preferably each R9 is independently hydrogen or Ci-Csalkyl, more preferably hydrogen or methyl, most preferably hydrogen. Preferably each R10 is independently methyl, hydrogen or cyano, e.g. hydrogen or cyano, preferably methyl or hydrogen, e.g. hydrogen.
Preferably each R11 is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro or methyl, most preferably chloro, fluoro or methyl. Preferably each R12 is independently bromo, chloro, fluoro, cyano, nitro, methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy, more preferably bromo, chloro, fluoro, nitro or methyl, most preferably chloro, fluoro or methyl. Preferably each R13 is independently methyl. Preferably m is 0 or 1, most preferably 0. A group of preferred compounds are those wherein A1, A2, A3 and A4 are independently of each other C-H or C-R5, preferably A1 is C-R5, A2 is C-H, A3 is C-H or nitrogen and A4 is C-H or nitrogen; G is oxygen;
R1 is hydrogen, methyl, ethyl, methylcarbonyl- or methoxycarbonyl-; R2 is a group of formula (Ha)
where L is a single bond, methylene methylene, ethylene or propylene, m is 0, 1, 2, 3, 4, or 5, and one of Y1 and Y2 is S, SO, SO2, S=N-R10, SO=N-R10 or C=N-OR10, and the other is CH2 in which each H may be replaced by R13. R3 is Ci-C8 haloalkyl;
R4 is phenyl substituted by one to three R7; each R5 is independently halogen, Ci-Csalkyl, Ci-Cshaloalkyl or Ci-Csalkenyl, or two R5 on adjacent carbon atoms together form a -CH=CH-CH=CH- bridge; each R7 is independently halogen, cyano, Ci-Csalkyl, Ci-Cshaloalkyl or Ci-Csalkoxy-; each R10 is independently methyl, hydrogen or cyano; R13 is Ci-Csalkyl,
Another group of preferred compounds are those wherein
A1, A2, A3 and A4 are independently of each other C-H or C-R5, preferably A1 is C- R5, A2 is C-H, A3 is C-H and A4 is C-H; G is oxygen;
R1 is hydrogen, methyl or ethyl; R2 is a group of formula (lib)
R13 where
L is a single bond methylene, ethylene or propylene, one of Y1 and Y2 is S, SO, SO2, S=N-R10, SO=N-R10 or C=N-OR10 and the other is CH2;
R3 is chlorodifluoromethyl or trifluoromethyl; R4 is 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-,
3,4-dichloro-phenyl-, 3,4,5-trichloro-phenyl- or 3-trifluoromethyl-phenyl-; each R5 is independently bromo, chloro, fluoro, methyl, trifluoromethyl or vinyl, or two R5 on adjacent carbon atoms together form a -CH=CH-CH=CH- bridge; each R10 is independently methyl or hydrogen; R13 is hydrogen or Ci-C8alkyl.
Yet another group of preferred compounds are those wherein A1, A2, A3 and A4 are independently of each other C-H or C-R5, preferably A1 is C-
R5, A2 is C-H, A3 is C-H and A4 is C-H; G is oxygen; R1 is hydrogen; R2 is a group of formula (lie)
where m is O, 1, 2, 3, 4, or 5, and Y2 is S, SO, SO2, or C=N-OR10; R3 is chlorodifluoromethyl or trifluoromethyl;
R4 is 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-, 3,4-dichloro-phenyl-, 3,4,5-trichloro-phenyl- or 3-trifluoromethyl-phenyl-; each R5 is independently bromo, chloro, fluoro, methyl, trifluoromethyl or vinyl, or two R5 on adjacent carbon atoms together form a -CH=CH-CH=CH- bridge; each R10 is independently methyl or hydrogen;
R13 is methyl.
A further group of preferred compounds are those wherein A1 is C-R5, A2 is C-H, A3 is C-H and A4 is C-H; G is oxygen;
R1 is hydrogen;
R2 is a group of formula (Hd)
where
Y2 is S, SO, SO2; R3 is trifluoromethyl;
R4 is 3,5-dichloro-phenyl; each R5 is independently methyl;
R13 is hydrogen or methyl.
In one preferred embodiment there is provided a compound of formula (Ia) where G, R1, R2, R3, R4 and R5 are as defined for a compound of formula (I); or a salt or TV- oxide thereof. The preferred values of G, L, R1, R2, R3, R4, Y1, Y2, Y3, R5, R6, R7, R8, R9, R10, R11, R12, R13 and m are as defined for a compound of formula (I).
In one preferred embodiment there is provided a compound of formula (Ib)
where G, R1, R2, R3 and R4 are as defined for a compound of formula (I); or a salt or TV-oxide thereof. The preferred values of G, L, R1, R2, R3, R4, Y1, Y2, Y3, R6, R7, R8, R9, R10, R11, R12, R13 and m are as defined for a compound of formula (I).
In one preferred embodiment there is provided a compound of formula (Ic)
where G, R1, R2, R3, R4 and R5 are as defined for a compound of formula (I); or a salt or TV- oxide thereof. The preferred values of G, L, R1, R2, R3, R4, Y1, Y2, Y3, R5, R6, R7, R8, R9, R10, R11, R12, R13 and m are as defined for a compound of formula (I).
Certain intermediates are novel and as such form a further aspect of the invention.
One group of novel intermediates are compounds of formula (IA)
wherein A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I); G is oxygen and R is Ci-C6alkoxy. The preferences for A1, A2, A3, A4, R1, R2, R3 and R4 are the same as the preferences set out for the corresponding substituents of a compound of formula
(I)-
A further group of novel intermediates are compounds of formula (VA)
wherein A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I); R is Ci- Cβalkoxy; and XA is a leaving group such as a halogen atom, preferably bromine or chlorine, more preferably bromine. The preferences for A1, A2, A3, A4, R3 and R4 are the same as the preferences set out for the corresponding substituents of a compound of formula (I). A further group of novel intermediates are compounds of formula (XIA)
wherein A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I); each R is independently Ci-Cβalkoxy; G is oxygen and XA is a leaving group such as a halogen atom, preferably bromine or chlorine, more preferably bromine. The preferences for A1, A2, A3, A4, R3 and R4 are the same as the preferences set out for the corresponding substituents of a compound of formula (I).
A further group of novel intermediates are compounds of formula (XVII)
wherein A1, A2, A3, A4, R1 and R2 are as defined for a compound of formula (I), R1', R2 and R3' are each independently optionally substituted alkyl or optionally substituted phenyl, preferably Ci-Cs alkyl, Ci-Cs haloalkyl, phenyl or phenyl optionally substituted with one to five groups independently selected from halogen and Ci-Cs alkyl, R4' is optionally substituted phenyl, optionally substituted alkyl, preferably Ci-Cs alkyl or Ci-Cs haloalkyl. The preferences for A1, A2, A3, A4, R1 and R2 are the same as the preferences set out for the corresponding substituents of a compound of formula (I). A further group of novel intermediates are compounds of formula (XX)
wherein A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I). The preferences for A1, A2, A3, A4, R1, R2, R3 and R4 are the same as the preferences set out for the corresponding substituents of a compound of formula (I).
A further group of novel intermediates are compounds of formula (XXIV)
wherein A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I); and XA is a leaving group such as a halogen atom, preferably bromine or chlorine, more preferably bromine. The preferences for A1, A2, A3, A4, R3 and R4 are the same as the preferences set out for the corresponding substituents of a compound of formula (I). A further group of novel intermediates are compounds of formula (XXVI)
wherein A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I); The preferences for A1, A2, A3, A4, R1, R2, R3 and R4 are the same as the preferences set out for the corresponding substituents of a compound of formula (I).
A further group of novel intermediates are compounds of formula (XXVII) wherein A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I); and XA is a leaving group such as a halogen atom, preferably bromine or chlorine, more preferably bromine. The preferences for A1, A2, A3, A4, R3 and R4 are the same as the preferences set out for the corresponding substituents of a compound of formula (I).
The compounds of the invention may be made by a variety of methods, for example, as shown in Scheme 1.
Scheme 1 reducing agent
(X) dehydrating agent
(VII) (VIII) catalyst R\ / CH,
(Vl)
CO hydrolysis
1) An amine of formula (IX) where A1, A2, A3 and A4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom, can be made by reacting a benzonitrile of formula (X) where A1, A2, A3 and A4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom, with a reducing agent, for example a metal hydride, such as lithium aluminum hydride, in a solvent, such as an aprotic solvent, such as diethyl ether. The reaction is carried out preferably under a protective atmosphere, such as an argon atmosphere. The reaction is carried out preferably at a temperature of from -200C to +1000C, more preferably from 00C to 800C, in particular at 400C. Benzonitriles of formula (X) are commercially available or can be made by methods known to a person skilled in the art.
2) A formamide of formula (VIII) where A1, A2, A3 and A4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom, can be made by reacting an amine of formula (IX) as defined under 1), with a formylating agent, such as ethyl formate, in a solvent, for example an excess of the formylating agent, in the presence of a base, for example an organic base, such as triethylamine. The reaction is carried out preferably at a temperature of from -200C to +1000C, more preferably from 200C to 900C, in particular at the reflux temperature of the solvent.
3) An isocyano compound of formula (VII) where A1, A2, A3 and A4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom, can be made by reacting a formamide of formula (VIII) as defined under 2), with a dehydrating agent, for example a chlorinating agent, such as phosphorus oxychloride, in a solvent, for example an aprotic solvent, such as dichloromethane. The reaction is carried out preferably at a temperature of from -200C to +500C, more preferably from 00C to 500C, in particular at ambient temperature.
4) A compound of formula (V) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom, can be made by reacting an isocyano compound of formula (VII) as defined under 3), with a vinyl compound of formula (VI) where R3 and R4 are as defined for a compound of formula (I), in the presence of a catalyst, such as copper(I) oxide, in a solvent, for example an aromatic solvent, such as toluene. The reaction is carried out preferably at a temperature of from -200C to +2000C, more preferably from 500C to 1500C, in particular at 1100C. Vinyl compounds of formula (VI) are known from the literature (for example, from EP 1 ,731 ,512) or can be made by methods known to a person skilled in the art. 5) A carboxylic ester of formula (IV) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I), G is oxygen and R is Ci-Csalkoxy, can be made by reacting a compound of formula (V) as defined under 4), with carbon monoxide and an alcohol of formula R-H where R is Ci-Csalkoxy, such as ethanol, in the presence of a catalyst, such as bis(triphenylphosphine)palladium(II) dichloride ("Pd(PPh3)2Cl2") or dichloro 1,1'- bis(diphenylphosphino)ferrocene palladium(II) dichloromethane adduct ("Pd(dppf)Cl2"), in the presence of a base, such as pyridine, triethylamine, 4-(dimethylamino)-pyridine ("DMAP"), diisopropylethylamine (Hunig's base) or sodium acetate, and optionally in the presence of a solvent, for example a polar solvent, such as dimethylformamide. The reaction is carried out preferably at a temperature of from -200C to +2000C, more preferably from 500C to 1500C, in particular at 85°C. The reaction is carried out preferably at a pressure of from 1 to 200 bar, more preferably from 2 to 10 bar, in particular at 6 bar.
6) A carboxylic acid of formula (III) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I), G is oxygen and R is OH, can be made from a carboxylic ester of formula (IV) as defined under 5), under standard conditions, such as treatment with an alkali hydroxide, such as sodium hydroxide or potassium hydroxide, in a solvent, such as ethanol or tetrahydrofuran, in the presence of water. Another alternative is the treatment of the ester with an acid, such as trifluoroacetic acid, in a solvent, such as dichloromethane, followed by addition of water. The reaction is carried out preferably at a temperature of from -200C to +1000C, more preferably from 200C to 800C, in particular at 500C.
7) An acid halide of formula (III1) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I), G is oxygen and R is Br, Cl or F, can be made from a carboxylic acid of formula (III) as defined under 5), under standard conditions, such as treatment with thionyl chloride or oxalyl chloride, in a solvent, such as dichloromethane. The reaction is carried out preferably at a temperature of from -200C to +1000C, more preferably from 00C to 500C, in particular at ambient temperature.
8) A compound of formula (I) where A , A , A , A , R , R , R and R are as defined for a compound of formula (I) and G is oxygen, can be made by reacting a carboxylic acid of formula (III) or an acid halide of formula (III1) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and G is oxygen, with an amine of formula HNR1R2 where R1 and R2 are as defined for a compound of formula (I). When a carboxylic acid is used, such reactions are usually carried out in the presence of a coupling reagent, such as N, N'- dicyclohexylcarbodiimide ("DCC"), 1 -ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride ("EDC") or bis(2-oxo-3-oxazolidinyl)phosphonic chloride ("BOP-Cl"), in the presence of a base, and optionally in the presence of a nucleophilic catalyst. Such reactions are carried out preferably at a temperature of from -200C to +2000C, more preferably from 500C to 1500C, in particular at 1000C. When an acid halide is used, such reactions are usually carried out in the presence of a base, and optionally in the presence of a nucleophilic catalyst. Alternatively, when an acid halide is used it is possible to conduct the reaction in a biphasic system comprising an organic solvent, preferably ethyl acetate, and an aqueous solvent, preferably a solution of sodium hydrogen carbonate. Such reactions are carried out preferably at a temperature of from -200C to +500C, more preferably from 00C to 500C, in particular at ambient temperature. Suitable nucleophilic catalysts include hydroxy- benzotriazole ("HOBT"). Suitable solvents include dimethylacetamide, tetrahydrofuran, dioxane, 1 ,2-dimethoxyethane, ethyl acetate and toluene. Amines of formula (II) are known from the literature (for example, from WO 2007/080131) or can be made by methods known to a person skilled in the art.
9) A compound of formula (I) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) and G is sulfur, can be made by reacting a compound of formula (III) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I), G is oxygen, or a compound of formula (HF) wherein R is Br, Cl or F, or a compound of formula (XI) wherein R is Ci-Csalkoxy (see Scheme 2), with a thio-transfer reagent, such as Fawesson's reagent or phosphorus pentasulfide, prior to reacting with the amine of formula FFNR1R2 as described under 8).
Scheme Ia
(VA) hydrolysis decaboxylation
(V) 9a) Alternatively a compound of formula (V) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom can be made by treatment of a compound of formula (VA) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom and R is Ci-Cβalkoxy under hydrolytic conditions followed by decarboxylation of the acid intermediate. Such conditions are, for example, treatment with an alkali hydroxide, such as sodium hydroxide or potassium hydroxide, in a solvent, such as ethanol or tetrahydrofuran, in the presence of water. Another alternative is the treatment of the ester with an acid, such as trifluoroacetic acid, in a solvent, such as dichloromethane, followed by addition of water. The reaction is carried out preferably at a temperature of from -200C to +1000C, more preferably from 200C to 800C, in particular at 500C.
9b) A compound of formula (VA) as A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom, can be made by reacting an isocyano compound of formula (VII) as defined under 3), with a vinyl compound of formula (VIA) where R3 and R4 are as defined for a compound of formula (I) and R is Ci-Cβalkoxy, in the presence of a catalyst, such as copper(I) oxide, in a solvent, for example an aromatic solvent, such as toluene. The reaction is carried out preferably at a temperature of from -200C to +2000C, more preferably from 500C to 1500C, in particular at 1100C. Vinyl compounds of formula (VIA) are known from the literature (for example, from J. Org. Chem. (2003), 68(15), 5925-5929) or can be made by methods known to a person skilled in the art.
Scheme 2
10) A compound of formula (XIV) where A1, A2, A3, A4 are as defined for a compound of formula (I), R is Ci-Cβalkoxy, R1', R2' and R3' represent optionally substituted alkyl or optionally substituted phenyl and G is oxygen, can be made by reacting a carboxylic acid of formula (XV) where A1, A2, A3, A4 are as defined for a compound of formula (I) and R is Ci-Cβalkoxy, with an amine (XVI) where R1', R2' and R3' represent optionally substituted alkyl or optionally substituted phenyl. Such reactions are usually carried out in the presence of a coupling reagent, such as N,N'-dicyclohexylcarbodiimide ("DCC"), l-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride ("EDC") or bis(2- oxo-3-oxazolidinyl)phosphonic chloride ("BOP-Cl"), in the presence of a base, and optionally in the presence of a nucleophilic catalyst. Such reactions are carried out preferably at a temperature of from -200C to +2000C, more preferably from 500C to 1500C, in particular at 1000C. Suitable nucleophilic catalysts include hydroxybenzotriazole ("HOBT"). Suitable solvents include dimethylacetamide, tetrahydrofuran, dioxane, 1,2- dimethoxyethane, ethyl acetate and toluene. Amines of formula (XVI) and carboxylic acids of formula (XV) are known from the literature or can be made by methods known to a person skilled in the art. H) A compound of formula (XIII) where A1, A2, A3, A4 are as defined for a compound of formula (I) R is Ci-Cβalkoxy, R1 ', R2'and R3' represent optionally substituted alkyl or optionally substituted phenyl and G is oxygen can be made by reacting a compound of formula (XIV) where A1, A2, A3, A4 are as defined for a compound of formula (I) R is Ci-Cβalkoxy, R1 ', R2' and R3' represent optionally substituted alkyl or optionally substituted phenyl and G is oxygen , with a thio-transfer reagent, such as Lawesson's reagent or phosphorus pentasulfϊde in a solvent, for example an aromatic solvent, such as toluene. The reaction is carried out preferably at a temperature of from -200C to +2000C, more preferably from 500C to 1500C, in particular at 1100C. 12) A compound of formula (XII) where A1, A2, A3, A4 are as defined for a compound of formula (I) R is Ci-Cβalkoxy, R1 ', R2 'and R3' represent optionally substituted alkyl or optionally substituted phenyl, R4' represents optionally substituted alkyl and G is oxygen can be made by reacting a compound of formula (XIII) where A1, A2, A3, A4 are as defined for a compound of formula (I) R is Ci-Cβalkoxy, R1 ', R2 'and R3' represent optionally substituted alkyl or optionally substituted phenyl and G is oxygen with an alkylating agent R4' -X where X is a leaving group for example a halogen atom, such as an iodine atom and a base such as sodium carbonate or potassium carbonate in a solvent, such as acetonitrile. The reaction is carried out preferably at a temperature of from -200C to +1000C, more preferably from 00C to 500C, in particular at ambient temperature. 13) A compound of formula (XI) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I), G is oxygen and R is Ci-Cβalkoxy can be made by reacting a compound of formula (XII) where A1, A2, A3, A4 are as defined for a compound of formula (I) R is Ci-Cβalkoxy, R1 ', R2 'and R3' represent optionally substituted alkyl or optionally substituted phenyl, R4' represents optionally substituted alkyl and G is oxygen with a vinyl compound of formula (VI) where R3 and R4 are as defined for a compound of formula (I), in the presence of a fluorine reagent such as potassium fluoride or tetrabutylammonium fluoride, in a solvent, for example THF. The reaction is carried out preferably at a temperature of from -200C to +5000C, more preferably from 00C to 1000C, in particular at ambient temperature. Vinyl compounds of formula (VI) are known from the literature (for example, from EP 1 ,731 ,512) or can be made by methods known to a person skilled in the art.
14) A compound of formula (I) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) and G is oxygen, can be made by reacting a carboxylic acid of formula (III) or an acid halide of formula (IH') where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I), G is oxygen and R is Br, Cl or F (which can be obtained from a compound of the formula (XI) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I), G is oxygen and R is Ci-Cβalkoxy), with an amine of formula HNR1R2 where R1 and R2 are as defined for a compound of formula (I) under conditions described under 8).
Scheme 2a
Fluorinating agent
Hydrolysis Decarboxylation
14a) Alternatively a compound of formula (III) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and G is Oxygen can be made by treatment of a compound of formula (XIA) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and R is Ci-Cβalkoxy under hydrolytic conditions followed by decarboxylation. Such conditions are, for example, treatment with an alkali hydroxide, such as sodium hydroxide or potassium hydroxide, in a solvent, such as ethanol or tetrahydrofuran, in the presence of water. Another alternative is the treatment of the ester with an acid, such as trifluoroacetic acid, in a solvent, such as dichloromethane, followed by addition of water. The reaction is carried out preferably at a temperature of from -200C to +1000C, more preferably from 200C to 800C, in particular at 500C.
14b) A compound of formula (XIA) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and R is Ci-Cβalkoxy , can be made reacting a compound of formula (XII) where A1, A2, A3, A4 are as defined for a compound of formula (I) R is C1- Cβalkoxy, R1', R2 'and R3' represent optionally substituted alkyl or optionally substituted phenyl, R4' represents optionally substituted alkyl and G is oxygen with a vinyl compound of formula (VIA) where R3 and R4 are as defined for a compound of formula (I) and R is Ci-
Cβalkoxy, in the presence of a fluorine reagent such as potassium fluoride or tetrabutylammonium fluoride, in a solvent, for example THF. The reaction is carried out preferably at a temperature of from -200C to +5000C, more preferably from 00C to 1000C, in particular at ambient temperature. Vinyl compounds of formula (VIA) are known from the literature (for example, from J. Org. Chem. (2003), 68(15), 5925-5929) or can be made by methods known to a person skilled in the art.
Scheme 3
(XVII I) (XVII)
Fluorinating agent (Vi;
(I) 15) Carboxylic acids of formula (XVIII) where A1, A2, A3, A4 are as defined for a compound of formula (I), R1', R2 'and R3' represent optionally substituted alkyl or optionally substituted phenyl, R4' represents optionally substituted alkyl and G is oxygen may be formed from esters of formula (XII), wherein R is Ci-Cβalkoxy. It is known to a person skilled in the art that there are many methods for the hydrolysis of such esters depending on the nature of the alkoxy group. One widely used method to achieve such a transformation is the treatment of the ester with an alkali hydroxide, such as sodium hydroxide or lithium hydroxide, in a solvent, such as ethanol or tetrahydrofuran, in the presence of water. Another is the treatment of the ester with an acid, such as trifluoro acetic acid, in a solvent, such as dichloromethane, followed by addition of water. The reaction is carried out at temperatures of from 00C to 1500C, preferably from 15°C to 1000C, in particular at 500C.
16) A compound of formula (XVII) where A1, A2, A3, A4 are as defined for a compound of formula (I), R1', R2'and R3' represent optionally substituted alkyl or optionally substituted phenyl, R4' represents optionally substituted alkyl and G is oxygen may be formed by reaction of acids of formula (XVIII) where A1, A2, A3, A4 are as defined for a compound of formula (I), R1', R2 'and R3' represent optionally substituted alkyl or optionally substituted phenyl, R4' represents optionally substituted alkyl and G is oxygen with an amine of formula HNR1R2 where R1 and R2 are as defined for a compound of formula (I) under conditions described under 8). 17) A compound of formula (I) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) and G is oxygen, can be made by reacting a compound of the formula (XVII) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I), G is oxygen, R1', R2'and R3' represent optionally substituted alkyl or optionally substituted phenyl and R4' represents optionally substituted alkyl with a vinyl compound of formula (VI) where R3 and R4 are as defined for a compound of formula (I), in the presence of a fluorine reagent such as potassium fluoride or tetrabutylammonium fluoride, in a solvent, for example THF under conditions described under 13).
Scheme 3a
hydrolysis decarboxylation
(I) 17a) Alternatively a compound of formula (I) where A1, A2, A3, A4, R3 and R4 are as defined herein and G is oxygen can be made by treatment of a compound of formula (IA) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I), G is oxygen, and R is Ci-Cβalkoxy, under hydrolytic conditions followed by decarboxylation. Such conditions are, for example, treatment with an alkali hydroxide, such as sodium hydroxide or potassium hydroxide, in a solvent, such as ethanol or tetrahydrofuran, in the presence of water. Another alternative is the treatment of the ester with an acid, such as trifluoroacetic acid, in a solvent, such as dichloromethane, followed by addition of water. The reaction is carried out preferably at a temperature of from -200C to +1000C, more preferably from 200C to 800C, in particular at 500C.
17b) A compound of formula (IA) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I), G is oxygen, and R is Ci-Cβalkoxy, can be made reacting a compound of formula (XVII) where A1, A2, A3, A4 are as defined for a compound of formula (I), R1', R2 'and R3' represent optionally substituted alkyl or optionally substituted phenyl, R4' represents optionally substituted alkyl and G is oxygen with a vinyl compound of formula (VIA) where R3 and R4 are as defined for a compound of formula (I) and R is Ci- Cβalkoxy , in the presence of a fluorine reagent such as potassium fluoride or tetrabutylammonium fluoride, in a solvent, for example THF. The reaction is carried out preferably at a temperature of from -200C to +5000C, more preferably from 00C to 1000C, in particular at ambient temperature. Vinyl compounds of formula (VIA) are known from the literature (for example, from J. Org. Chem. (2003), 68(15), 5925-5929) or can be made by methods known to a person skilled in the art. Scheme 4
(XIX) (I)
18) A compound of formula (I) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined herein and G is oxygen, can be made by reacting a compound of the formula (XX) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) and G is oxygen, with a reducing agent such as Zn/HCl, in a solvent, for example water or DMF or mixtures thereof. The reaction is carried out preferably at a temperature of from -200C to +5000C, more preferably from 00C to 1000C, in particular at 800C.
19) A compound of formula (XX) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) and G is oxygen, can be made by reacting a compound of the formula (XXI) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) and G is oxygen (which may be prepared according to the methods described in WO 2009/080250) with nitromethane in the presence of a base such as NaOH, in a solvent, for example water or DMF or mixtures thereof. The reaction is carried out preferably at a temperature of from -200C to +5000C, more preferably from 00C to 1000C, in particular at ambient temperature. 20) Alternatively, a compound of formula (I) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined herein and G is oxygen, as shown in Scheme 4 can be prepared from a compound of the formula (XX) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) and G is oxygen via an intermediate (XIX) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) and G is oxygen, for example under reaction conditions described under 18).
Representative experimental conditions for this transformation are also described in Tetrahedron Letters 2003, 44, 3701-3703.
Scheme 5
(XXV) (XXIV) reducing agent reducing agent
reducing agent
(I)
21) A compound of formula (III) where A 1 , A \ 2 , A , A , R a „„nd,} T R-j 4 are as defined for a compound of formula (I), G is oxygen can be made from an compound of the formula (XI) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I), G is oxygen and R is Ci-Cβalkoxy under conditions described under 6)
22) A compound of formula (XI) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I), G is oxygen and R is Ci-Cβalkoxy can be made by reacting a compound of formula (XXII) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen as described under 5).
23) A compound of formula (XXII) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen, can be made by reacting a compound of the formula
(XXIV) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen under conditions as described under 18).
24) Alternatively, compounds of formula (XXII) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen, as shown in Scheme 5 can be prepared from a compound of the formula (XXIV) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen via an intermediate (XIII) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen for example under reaction conditions described under 18).
25) A compound of formula (XXIV) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen, can be made by reacting a compound of the formula
(XXV) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen (which may be prepared according to the methods described in WO 2009/080250) under conditions as described under 19). Scheme 6
26) Alternatively, a compound of formula (I) where R are as defined for a compound of formula (I) and G is oxygen, can be made by reacting a compound of the formula (XXVI) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) and G is oxygen, with a reducing agent such as Raney Ni /H2, in a solvent, for example methanol or ethanol. The reaction is carried out preferably at a temperature of from -200C to +5000C, more preferably from 00C to 1000C. Representative experimental conditions for this transformation are described by Allen, C.F.H. and Wilson, CV. in Org Synth. (1947), 27.
27) A compound of formula (XXVI) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) and G is oxygen, can be made by reacting a compound of the formula (XXI) where A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) and G is oxygen (which may be prepared according to the methods described in WO 2009/080250) with a cyanide source such as sodium cyanide, potassium cyanide, trimethylsilyl cyanide, acetone cyanohydrin, or diethylaluminium cyanide, in a solvent, for example toluene, tetrahydrofuran, acetone, acetic acid, ethanol, or water or mixtures thereof. The reaction is carried out preferably at a temperature of from -200C to +5000C, more preferably from 00C to 1000C, in particular at ambient temperature. Representative experimental conditions for this transformation are described in Tetrahedron, 64(17), 3642-3654; 2008. Scheme 7
(XXV) (XXVI I)
reducing agent
(XXI I)
28) A compound of formula (XXII) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen, can be made by reacting a compound of the formula (XXVII) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen (which may be prepared according to the methods described in WO 2009/080250) under conditions as described under 26).
29) A compound of formula (XXVII) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen, can be made by reacting a compound of the formula (XXV) where A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) and XA is a leaving group, for example a halogen atom, such as a bromine atom and G is oxygen under conditions as described under 27).
Compounds of formula (I) contain a chiral centre giving rise to enantiomers of the formula (I*) and (I**).
Enantiomerically enriched mixtures of compounds of formula (I*) or (I**) may be prepared, for example, according to schemes 4 or 5 by formation of intermediate XX or XXIV via an asymmetric Michael addition, see for example J. Org. Chem. 2008, 73, 3475-3480 and references cited therein". Alternatively, such enantiomerically enriched mixtures may be prepared according to schemes 6 or 7 by stereoselective addition of cyanide, see for example J. Am. Chem. Soc. 2008, 130, 6072-6073.
A compound of formula (I) may be a mixture of compounds I* and I** in any ratio e.g. in a molar ratio of 1 :99 to 99:1, e.g. 10:1 to 1 :10, e.g. a substantially 50:50 molar ratio. For example, in an enantiomerically enriched mixture of formula I**, the molar proportion of compound I** compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%. Likewise, in an enantiomerically enriched mixture of formula I*, the molar proportion of the compound of formula I* compared to the total amount of both enantiomers is for example greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%.
The compounds of formula (I) can be used to control infestations of insect pests such as Lepidoptera, Diptera, Hemiptera, Thysanoptera, Orthoptera, Dictyoptera, Coleoptera, Siphonaptera, Hymenoptera and Isoptera and also other invertebrate pests, for example, acarine, nematode and mollusc pests. Insects, acarines, nematodes and molluscs are hereinafter collectively referred to as pests. The pests which may be controlled by the use of the invention compounds include those pests associated with agriculture (which term includes the growing of crops for food and fiber products), horticulture and animal husbandry, companion animals, forestry and the storage of products of vegetable origin (such as fruit, grain and timber); those pests associated with the damage of man-made structures and the transmission of diseases of man and animals; and also nuisance pests (such as flies). The compounds of the invention may be used for example on turf, ornamentals, such as flowers, shrubs, broad-leaved trees or evergreens, for example conifers, as well as for tree injection, pest management and the like.
Examples of pest species which may be controlled by the compounds of formula (I) include: Myzus persicae (aphid), Aphis gossypii (aphid), Aphis fabae (aphid), Lygus spp.
(capsids), Dysdercus spp. (capsids), Nilaparvata lugens (planthopper), Nephotettixc incticeps (leafhopper), Nezara spp. (stinkbugs), Euschistus spp. (stinkbugs), Leptocorisa spp. (stinkbugs), Frankliniella occidentalis (thrip), Thrips spp. (thrips), Leptinotarsa decemlineata (Colorado potato beetle), Anthonomus grandis (boll weevil), Aonidiella spp. (scale insects), Trialeurodes spp. (white flies), Bemisia tabaci (white fly), Ostrinia nubilalis (European corn borer), Spodoptera littoralis (cotton leafworm), Heliothis virescens (tobacco budworm), Helicoverpa armigera (cotton bollworm), Helicoverpa zea (cotton bollworm), Sylepta derogata (cotton leaf roller), Pieris brassicae (white butterfly), Plutella xylostella (diamond back moth), Agrotis spp. (cutworms), Chilo suppressalis (rice stem borer), Locusta_ migratoria (locust), Chortiocetes terminifera (locust), Diabrotica spp. (rootworms), Panonychus ulmi (European red mite), Panonychus citri (citrus red mite), Tetranychus urticae (two-spotted spider mite), Tetranychus cinnabarinus (carmine spider mite), Phyllocoptruta oleivora (citrus rust mite), Polyphagotarsonemus latus (broad mite), Brevipalpus spp. (flat mites), Boophilus microplus (cattle tick), Dermacentor variabilis (American dog tick), Ctenocephalides felis (cat flea), Liriomyza spp. (leafminer), Musca domestica (housefly), Aedes aegypti (mosquito), Anopheles spp. (mosquitoes), Culex spp. (mosquitoes), Lucillia spp. (blowflies), Blattella germanica (cockroach), Periplaneta americana (cockroach), Blatta orientalis (cockroach), termites of the Mastotermitidae (for example Mastotermes spp.), the Kalotermitidae (for example Neotermes spp.), the Rhinotermitidae (for example Coptotermes formosanus, Reticulitertn.es flavipes, R. speratu, R. virginicus, R. hesperus, and R. santonensis) and the Termitidae (for example Globitermes sulfur eus), Solenopsis geminata (fire ant), Monomorium pharaonis (pharaoh's ant), Damalinia spp. and Linognathus spp. (biting and sucking lice), Meloidogyne spp. (root knot nematodes), Globodera spp. and Heterodera spp. (cyst nematodes), Pratylenchus spp. (lesion nematodes), Rhodopholus spp. (banana burrowing nematodes), Tylenchulus spp. (citrus nematodes), Haemonchus contortus (barber pole worm), Caenorhabditis elegans_ (vinegar eelworm), Trichostrongylus spp. (gastro intestinal nematodes) and Deroceras reticulatum (slug). The invention therefore provides a method of controlling insects, acarines, nematodes or molluscs which comprises applying an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I), or a composition containing a compound of formula (I), to a pest, a locus of pest, preferably a plant, or to a plant susceptible to attack by a pest. The compounds of formula (I) are preferably used against insects or acarines. The compounds of the invention may also be used for controlling insects that are resistant to known insecticides.
The term "plant" as used herein includes seedlings, bushes and trees.
Crops are to be understood as also including those crops which have been rendered tolerant to herbicides or classes of herbicides (e.g. ALS-, GS-, EPSPS-, PPO- and HPPD- inhibitors) by conventional methods of breeding or by genetic engineering. An example of a crop that has been rendered tolerant to imidazolinones, e.g. imazamox, by conventional methods of breeding is Clearfϊeld® summer rape (canola). Examples of crops that have been rendered tolerant to herbicides by genetic engineering methods include e.g. glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady® and LibertyLink®.
Crops are also to be understood as being those which have been rendered resistant to harmful insects by genetic engineering methods, for example Bt maize (resistant to European corn borer), Bt cotton (resistant to cotton boll weevil) and also Bt potatoes (resistant to Colorado beetle). Examples of Bt maize are the Bt 176 maize hybrids of NK® (Syngenta Seeds). Examples of transgenic plants comprising one or more genes that code for an insecticidal resistance and express one or more toxins are KnockOut® (maize), Yield Gard® (maize), NuCOTIN33B® (cotton), Bollgard® (cotton), NewLeaf® (potatoes), NatureGard® and Protexcta®. Plant crops or seed material thereof can be both resistant to herbicides and, at the same time, resistant to insect feeding ("stacked" transgenic events). For example, seed can have the ability to express an insecticidal Cry3 protein while at the same time being tolerant to glyphosate.
Crops are also to be understood as being those which are obtained by conventional methods of breeding or genetic engineering and contain so-called output traits (e.g. improved storage stability, higher nutritional value and improved flavor).
In order to apply a compound of formula (I) as an insecticide, acaricide, nematicide or molluscicide to a pest, a locus of pest, or to a plant susceptible to attack by a pest, a compound of formula (I) is usually formulated into a composition which includes, in addition to the compound of formula (I), a suitable inert diluent or carrier and, optionally, a surface active agent (SFA). SFAs are chemicals which are able to modify the properties of an interface (for example, liquid/solid, liquid/air or liquid/liquid interfaces) by lowering the interfacial tension and thereby leading to changes in other properties (for example dispersion, emulsification and wetting). It is preferred that all compositions (both solid and liquid formulations) comprise, by weight, 0.0001 to 95%, more preferably 1 to 85%, for example 5 to 60%, of a compound of formula (I). The composition is generally used for the control of pests such that a compound of formula (I) is applied at a rate of from O.lg to 10kg per hectare, preferably from Ig to 6kg per hectare, more preferably from Ig to lkg per hectare. When used in a seed dressing, a compound of formula (I) is used at a rate of O.OOOlg to 1Og (for example 0.00 Ig or 0.05g), preferably 0.005g to 1Og, more preferably 0.005g to 4g, per kilogram of seed.
In another aspect the present invention provides an insecticidal, acaricidal, nematicidal or molluscicidal composition comprising an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I) and for example a suitable carrier or diluent therefor. The composition is preferably an insecticidal or acaricidal composition.
The compositions can be chosen from a number of formulation types, including dustable powders (DP), soluble powders (SP), water soluble granules (SG), water dispersible granules (WG), wettable powders (WP), granules (GR) (slow or fast release), soluble concentrates (SL), oil miscible liquids (OL), ultra low volume liquids (UL), emulsifϊable concentrates (EC), dispersible concentrates (DC), emulsions (both oil in water (EW) and water in oil (EO)), micro-emulsions (ME), suspension concentrates (SC), aerosols, fogging/smoke formulations, capsule suspensions (CS) and seed treatment formulations. The formulation type chosen in any instance will depend upon the particular purpose envisaged and the physical, chemical and biological properties of the compound of formula (I).
Dustable powders (DP) may be prepared by mixing a compound of formula (I) with one or more solid diluents (for example natural clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk, diatomaceous earths, calcium phosphates, calcium and magnesium carbonates, sulfur, lime, flours, talc and other organic and inorganic solid carriers) and mechanically grinding the mixture to a fine powder.
Soluble powders (SP) may be prepared by mixing a compound of formula (I) with one or more water-soluble inorganic salts (such as sodium bicarbonate, sodium carbonate or magnesium sulfate) or one or more water-soluble organic solids (such as a polysaccharide) and, optionally, one or more wetting agents, one or more dispersing agents or a mixture of said agents to improve water dispersibility/solubility. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water soluble granules (SG).
Wettable powders (WP) may be prepared by mixing a compound of formula (I) with one or more solid diluents or carriers, one or more wetting agents and, preferably, one or more dispersing agents and, optionally, one or more suspending agents to facilitate the dispersion in liquids. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water dispersible granules (WG).
Granules (GR) may be formed either by granulating a mixture of a compound of formula (I) and one or more powdered solid diluents or carriers, or from pre-formed blank granules by absorbing a compound of formula (I) (or a solution thereof, in a suitable agent) in a porous granular material (such as pumice, attapulgite clays, fuller's earth, kieselguhr, diatomaceous earths or ground corn cobs) or by adsorbing a compound of formula (I) (or a solution thereof, in a suitable agent) on to a hard core material (such as sands, silicates, mineral carbonates, sulfates or phosphates) and drying if necessary. Agents which are commonly used to aid absorption or adsorption include solvents (such as aliphatic and aromatic petroleum solvents, alcohols, ethers, ketones and esters) and sticking agents (such as polyvinyl acetates, polyvinyl alcohols, dextrins, sugars and vegetable oils). One or more other additives may also be included in granules (for example an emulsifying agent, wetting agent or dispersing agent).
Dispersible Concentrates (DC) may be prepared by dissolving a compound of formula (I) in water or an organic solvent, such as a ketone, alcohol or glycol ether. These solutions may contain a surface active agent (for example to improve water dilution or prevent crystallization in a spray tank). Emulsifϊable concentrates (EC) or oil- in- water emulsions (EW) may be prepared by dissolving a compound of formula (I) in an organic solvent (optionally containing one or more wetting agents, one or more emulsifying agents or a mixture of said agents). Suitable organic solvents for use in ECs include aromatic hydrocarbons (such as alkylbenzenes or alkylnaphthalenes, exemplified by SOLVESSO 100, SOLVESSO 150 and SOLVESSO 200; SOLVESSO is a Registered Trade Mark), ketones (such as cyclohexanone or methylcyclohexanone) and alcohols (such as benzyl alcohol, furfuryl alcohol or butanol), JV-alkylpyrrolidones (such as JV-methylpyrrolidone or JV-octylpyrrolidone), dimethyl amides of fatty acids (such as Cs-Cio fatty acid dimethylamide) and chlorinated hydrocarbons. An EC product may spontaneously emulsify on addition to water, to produce an emulsion with suffϊcient stability to allow spray application through appropriate equipment. Preparation of an EW involves obtaining a compound of formula (I) either as a liquid (if it is not a liquid at room temperature, it may be melted at a reasonable temperature, typically below 700C) or in solution (by dissolving it in an appropriate solvent) and then emulsifiying the resultant liquid or solution into water containing one or more SFAs, under high shear, to produce an emulsion. Suitable solvents for use in EWs include vegetable oils, chlorinated hydrocarbons (such as chlorobenzenes), aromatic solvents (such as alkylbenzenes or alkylnaphthalenes) and other appropriate organic solvents which have a low solubility in water.
Microemulsions (ME) may be prepared by mixing water with a blend of one or more solvents with one or more SFAs, to produce spontaneously a thermodynamically stable isotropic liquid formulation. A compound of formula (I) is present initially in either the water or the solvent/SFA blend. Suitable solvents for use in MEs include those hereinbefore described for use in ECs or in EWs. An ME may be either an oil-in-water or a water-in-oil system (which system is present may be determined by conductivity measurements) and may be suitable for mixing water-soluble and oil- soluble pesticides in the same formulation. An ME is suitable for dilution into water, either remaining as a microemulsion or forming a conventional oil-in-water emulsion.
Suspension concentrates (SC) may comprise aqueous or non-aqueous suspensions of finely divided insoluble solid particles of a compound of formula (I). SCs may be prepared by ball or bead milling the solid compound of formula (I) in a suitable medium, optionally with one or more dispersing agents, to produce a fine particle suspension of the compound. One or more wetting agents may be included in the composition and a suspending agent may be included to reduce the rate at which the particles settle. Alternatively, a compound of formula (I) may be dry milled and added to water, containing agents hereinbefore described, to produce the desired end product.
Aerosol formulations comprise a compound of formula (I) and a suitable propellant (for example /? -butane). A compound of formula (I) may also be dissolved or dispersed in a suitable medium (for example water or a water miscible liquid, such as n-propanol) to provide compositions for use in non-pressurized, hand-actuated spray pumps. A compound of formula (I) may be mixed in the dry state with a pyrotechnic mixture to form a composition suitable for generating, in an enclosed space, a smoke containing the compound.
Capsule suspensions (CS) may be prepared in a manner similar to the preparation of EW formulations but with an additional polymerization stage such that an aqueous dispersion of oil droplets is obtained, in which each oil droplet is encapsulated by a polymeric shell and contains a compound of formula (I) and, optionally, a carrier or diluent therefor. The polymeric shell may be produced by either an interfacial poly condensation reaction or by a coacervation procedure. The compositions may provide for controlled release of the compound of formula (I) and they may be used for seed treatment. A compound of formula (I) may also be formulated in a biodegradable polymeric matrix to provide a slow, controlled release of the compound.
A composition may include one or more additives to improve the biological performance of the composition (for example by improving wetting, retention or distribution on surfaces; resistance to rain on treated surfaces; or uptake or mobility of a compound of formula (I)). Such additives include surface active agents, spray additives based on oils, for example certain mineral oils or natural plant oils (such as soy bean and rape seed oil), and blends of these with other bio-enhancing adjuvants (ingredients which may aid or modify the action of a compound of formula (I)). A compound of formula (I) may also be formulated for use as a seed treatment, for example as a powder composition, including a powder for dry seed treatment (DS), a water soluble powder (SS) or a water dispersible powder for slurry treatment (WS), or as a liquid composition, including a flowable concentrate (FS), a solution (LS) or a capsule suspension (CS). The preparations of DS, SS, WS, FS and LS compositions are very similar to those of, respectively, DP, SP, WP, SC and DC compositions described above. Compositions for treating seed may include an agent for assisting the adhesion of the composition to the seed (for example a mineral oil or a film-forming barrier).
Wetting agents, dispersing agents and emulsifying agents may be surface SFAs of the cationic, anionic, amphoteric or non-ionic type. Suitable SFAs of the cationic type include quaternary ammonium compounds (for example cetyltrimethyl ammonium bromide), imidazolines and amine salts.
Suitable anionic SFAs include alkali metals salts of fatty acids, salts of aliphatic monoesters of sulfuric acid (for example sodium lauryl sulfate), salts of sulfonated aromatic compounds (for example sodium dodecylbenzenesulfonate, calcium dodecylbenzenesulfonate, butylnaphthalene sulfonate and mixtures of sodium di-ώopropyl- and tri-ώopropyl-naphthalene sulfonates), ether sulfates, alcohol ether sulfates (for example sodium laureth-3-sulfate), ether carboxylates (for example sodium laureth-3-carboxylate), phosphate esters (products from the reaction between one or more fatty alcohols and phosphoric acid (predominately mono-esters) or phosphorus pentoxide (predominately di- esters), for example the reaction between lauryl alcohol and tetraphosphoric acid; additionally these products may be ethoxylated), sulfosuccinamates, paraffin or olefϊne sulfonates, taurates and lignosulfonates.
Suitable SFAs of the amphoteric type include betaines, propionates and glycinates. Suitable SFAs of the non- ionic type include condensation products of alkylene oxides, such as ethylene oxide, propylene oxide, butylene oxide or mixtures thereof, with fatty alcohols (such as oleyl alcohol or cetyl alcohol) or with alkylphenols (such as octylphenol, nonylphenol or octylcresol); partial esters derived from long chain fatty acids or hexitol anhydrides; condensation products of said partial esters with ethylene oxide; block polymers (comprising ethylene oxide and propylene oxide); alkanolamides; simple esters (for example fatty acid polyethylene glycol esters); amine oxides (for example lauryl dimethyl amine oxide); and lecithins.
Suitable suspending agents include hydrophilic colloids (such as polysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose) and swelling clays (such as bentonite or attapulgite).
A compound of formula (I) may be applied by any of the known means of applying pesticidal compounds. For example, it may be applied, formulated or unformulated, to the pests or to a locus of the pests (such as a habitat of the pests, or a growing plant liable to infestation by the pests) or to any part of the plant, including the foliage, stems, branches or roots, to the seed before it is planted or to other media in which plants are growing or are to be planted (such as soil surrounding the roots, the soil generally, paddy water or hydroponic culture systems), directly or it may be sprayed on, dusted on, applied by dipping, applied as a cream or paste formulation, applied as a vapor or applied through distribution or incorporation of a composition (such as a granular composition or a composition packed in a water-soluble bag) in soil or an aqueous environment.
A compound of formula (I) may also be injected into plants or sprayed onto vegetation using electrodynamic spraying techniques or other low volume methods, or applied by land or aerial irrigation systems.
Compositions for use as aqueous preparations (aqueous solutions or dispersions) are generally supplied in the form of a concentrate containing a high proportion of the active ingredient, the concentrate being added to water before use. These concentrates, which may include DCs, SCs, ECs, EWs, MEs, SGs, SPs, WPs, WGs and CSs, are often required to withstand storage for prolonged periods and, after such storage, to be capable of addition to water to form aqueous preparations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment. Such aqueous preparations may contain varying amounts of a compound of formula (I) (for example 0.0001 to 10%, by weight) depending upon the purpose for which they are to be used.
A compound of formula (I) may be used in mixtures with fertilizers (for example nitrogen-, potassium- or phosphorus-containing fertilizers). Suitable formulation types include granules of fertilizer. The mixtures preferably contain up to 25% by weight of the compound of formula (I).
The invention therefore also provides a fertilizer composition comprising a fertilizer and a compound of formula (I). The compositions of this invention may contain other compounds having biological activity, for example micronutrients or compounds having fungicidal activity or which possess plant growth regulating, herbicidal, insecticidal, nematicidal or acaricidal activity.
The compound of formula (I) may be the sole active ingredient of the composition or it may be admixed with one or more additional active ingredients such as a pesticide, fungicide, synergist, herbicide or plant growth regulator where appropriate. An additional active ingredient may: provide a composition having a broader spectrum of activity or increased persistence at a locus; synergize the activity or complement the activity (for example by increasing the speed of effect or overcoming repellency) of the compound of formula (I); or help to overcome or prevent the development of resistance to individual components. The particular additional active ingredient will depend upon the intended utility of the composition. Examples of suitable pesticides include the following: a) Pyrethroids, such as permethrin, cypermethrin, fenvalerate, esfenvalerate, deltamethrin, cyhalothrin (in particular lambda-cyhalothrin, gamma-cyhalothrin), bifenthrin, fenpropathrin, cyfluthrin, tefluthrin, fish safe pyrethroids (for example ethofenprox), natural pyrethrin, tetramethrin, S-bioallethrin, fenfluthrin, prallethrin or 5-benzyl-3-furylmethyl-(E)-(lR,3S)-2,2-dimethyl- 3 -(2-oxothio lan-3 -ylidenemethyl)cyclopropane carboxylate; b) Organophosphates, such as profenofos, sulprofos, acephate, methyl parathion, azinphos-methyl, demeton-s-methyl, heptenophos, thiometon, fenamiphos, monocrotophos, profenofos, triazophos, methamidophos, dimethoate, phosphamidon, malathion, chlorpyrifos, phosalone, terbufos, fensulfothion, fonofos, phorate, phoxim, pirimiphos-methyl, pirimiphos-ethyl, fenitrothion, fosthiazate or diazinon; c) Carbamates (including aryl carbamates), such as pirimicarb, triazamate, cloethocarb, carbofuran, furathiocarb, ethiofencarb, aldicarb, thiofurox, carbosulfan, bendiocarb, fenobucarb, propoxur, methomyl or oxamyl; d) Benzoyl ureas, such as diflubenzuron, triflumuron, hexaflumuron, flufenoxuron or chlorfluazuron; e) Organic tin compounds, such as cyhexatin, fenbutatin oxide or azocyclotin; f) Pyrazoles, such as tebufenpyrad and fenpyroximate; g) Macrolides, such as avermectins or milbemycins, for example abamectin, emamectin benzoate, ivermectin, milbemycin, spinosad, azadirachtin or spinetoram; h) Hormones or pheromones; i) Organochlorine compounds, such as endosulfan (in particular alpha-endosulfan), benzene hexachloride, DDT, chlordane or dieldrin; j) Amidines, such as chlordimeform or amitraz; k) Fumigant agents, such as chloropicrin, dichloropropane, methyl bromide or metam; 1) Neonicotinoid compounds, such as imidacloprid, thiacloprid, acetamiprid, nitenpyram, dinotefuran, thiamethoxam, clothianidin, nithiazine or flonicamid; m) Diacylhydrazines, such as tebufenozide, chromafenozide or methoxyfenozide; n) Diphenyl ethers, such as diofenolan or pyriproxifen; o) Indoxacarb; p) Chlorfenapyr; q) Pymetrozine; r) Spirotetramat, spirodiclofen or spiromesifen; s) Diamides, such as flubendiamide, chlorantraniliprole or cyantraniliprole; t) Sulfoxaflor; u) Metaflumizone; v) Fipronil and Ethiprole; or w) Pyrifluqinazon.
In addition to the major chemical classes of pesticide listed above, other pesticides having particular targets may be employed in the composition, if appropriate for the intended utility of the composition. For instance, selective insecticides for particular crops, for example stemborer specific insecticides (such as cartap) or hopper specific insecticides (such as buprofezin) for use in rice may be employed. Alternatively insecticides or acaricides specific for particular insect species/stages may also be included in the compositions (for example acaricidal ovo-larvicides, such as clofentezine, flubenzimine, hexythiazox or tetradifon; acaricidal motilicides, such as dicofol or propargite; acaricides, such as bromopropylate or chlorobenzilate; or growth regulators, such as hydramethylnon, cyromazine, methoprene, chlorfluazuron or diflubenzuron).
Examples of fungicidal compounds which may be included in the composition of the invention are (E)-Λ/-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy- iminoacetamide (SSF- 129), 4-bromo-2-cyano-N,Λ/-dimethyl-6-trifluoromethyl- benzimidazole- 1 -sulfonamide, α-[Λ/-(3-chloro-2,6-xylyl)-2-methoxyacetamido]-γ -butyro lactone, 4-chloro-2-cyano-Λ/,Λ/-dimethyl-5-/?-tolylimidazole- 1 -sulfonamide (IKF-916, cyamidazosulfamid), 3-5-dichloro-iV-(3-chloro- 1 -ethyl- 1 -methyl-2-oxopropyl)-4- methylbenzamide (RH-7281, zoxamide), Λ/-allyl-4,5,-dimethyl-2-trimethylsilylthiophene-3- carboxamide (MON65500), Λ/-(l-cyano-l,2-dimethylpropyl)-2-(2,4-dichlorophenoxy)- propionamide (AC382042), JV-(2-methoxy-5-pyridyl)-cyclopropane carboxamide, acibenzolar (CGA245704) (e.g. acibenzolar-S-methyl), alanycarb, aldimorph, anilazine, azaconazole, azoxystrobin, benalaxyl, benomyl, benthiavalicarb, biloxazol, bitertanol, bixafen, blasticidin S, boscalid, bromuconazole, bupirimate, captafol, captan, carbendazim, carbendazim chlorhydrate, carboxin, carpropamid, carvone, CGA41396, CGA41397, chinomethionate, chlorothalonil, chlorozolinate, clozylacon, copper containing compounds such as copper oxychloride, copper oxyquinolate, copper sulfate, copper tallate and Bordeaux mixture, cyclufenamid, cymoxanil, cyproconazole, cyprodinil, debacarb, di-2-pyridyl disulfide 1,1 '-dioxide, dichlofluanid, diclomezine, dicloran, diethofencarb, difenoconazole, difenzoquat, diflumetorim, 0,O-di-ώo-propyl-lS'-benzyl thiophosphate, dimefluazole, dimetconazole, dimethomorph, dimethirimol, diniconazole, dinocap, dithianon, dodecyl dimethyl ammonium chloride, dodemorph, dodine, doguadine, edifenphos, epoxiconazole, ethirimol, ethyl-(Z)-7V-benzyl-7V-([methyl(methyl-thioethylideneamino- oxycarbonyl)amino]thio)-β-alaninate, etridiazole, famoxadone, fenamidone (RPA407213), fenarimol, fenbuconazole, fenfuram, fenhexamid (KBR2738), fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumetover, fluopyram, fluoxastrobin, fluoroimide, fluquinconazole, flusilazole, flutolanil, flutriafol, fluxapyroxad, folpet, fuberidazole, furalaxyl, furametpyr, guazatine, hexaconazole, hydroxyisoxazole, hymexazole, imazalil, imibenconazole, iminoctadine, iminoctadine triacetate, ipconazole, iprobenfos, iprodione, iprovalicarb (SZX0722), isopropanyl butyl carbamate, isoprothiolane, isopyrazam, kasugamycin, kresoxim-methyl, LYl 86054, LY211795, LY248908, mancozeb, mandipropamid, maneb, mefenoxam, metalaxyl, mepanipyrim, mepronil, metalaxyl, metconazole, metiram, metiram-zinc, metominostrobin, myclobutanil, neoasozin, nickel dimethyldithiocarbamate, nitrothal-ώopropyl, nuarimol, ofurace, organomercury compounds, oxadixyl, oxasulfuron, oxolinic acid, oxpoconazole, oxycarboxin, pefurazoate, penconazole, pencycuron, penflufen, penthiopyrad, phenazin oxide, phosetyl-Al, phosphorus acids, phthalide, picoxystrobin (ZAl 963), polyoxinD, polyram, probenazole, prochloraz, procymidone, propamocarb, propiconazole, propineb, propionic acid, prothioconazole, pyrazophos, pyrifenox, pyrimethanil, pyraclostrobin, pyroquilon, pyroxyfur, pyrrolnitrin, quaternary ammonium compounds, quinomethionate, quinoxyfen, quintozene, sedaxane, sipconazole (F- 155), sodium pentachlorophenate, spiroxamine, streptomycin, sulfur, tebuconazole, tecloftalam, tecnazene, tetraconazole, thiabendazole, thifluzamid, 2-(thiocyanomethylthio)benzothiazole, thiophanate-methyl, thiram, timibenconazole, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triazbutil, triazoxide, tricyclazole, tridemorph, trifloxystrobin (CGA279202), triforine, triflumizole, triticonazole, validamycin A, vapam, vinclozolin, zineb and ziram, a compound of formula (A), a compound of formula (B) and a compound of formula (C)
The compounds of formula (I) may be mixed with soil, peat or other rooting media for the protection of plants against seed-borne, soil-borne or foliar fungal diseases.
Examples of suitable synergists for use in the compositions include piperonyl butoxide, sesamex, safroxan and dodecyl imidazole.
Suitable herbicides and plant-growth regulators for inclusion in the compositions will depend upon the intended target and the effect required.
An example of a rice selective herbicide which may be included is propanil. An example of a plant growth regulator for use in cotton is PIX™. Some mixtures may comprise active ingredients which have significantly different physical, chemical or biological properties such that they do not easily lend themselves to the same conventional formulation type. In these circumstances other formulation types may be prepared. For example, where one active ingredient is a water insoluble solid and the other a water insoluble liquid, it may nevertheless be possible to disperse each active ingredient in the same continuous aqueous phase by dispersing the solid active ingredient as a suspension
(using a preparation analogous to that of an SC) but dispersing the liquid active ingredient as an emulsion (using a preparation analogous to that of an EW). The resultant composition is a suspoemulsion (SE) formulation.
The following Examples illustrate, but do not limit, the invention.
Preparation Examples
The following abbreviations were used in this section: s = singlet; bs = broad singlet; d = doublet; dd = double doublet; dt = double triplet; t = triplet, tt = triple triplet, q = quartet, sept = septet; m = multiplet; Me = methyl; Et = ethyl; Pr = propyl; Bu = butyl; M.p. = melting point; RT = retention time, [M+H]+ = molecular mass of the molecular cation, [M-H]" = molecular mass of the molecular anion.
The following LC-MS methods were used to characterize the compounds: Method A
MS ZQ Mass Spectrometer from Waters (single quadrupole mass spectrometer), ionization method: electrospray, polarity: positive ionization, capillary (kV) 3.00, cone (V) 30.00, source temperature (0C) 100, desolvation temperature (0C) 250, cone gas flow (L/Hr) 50, desolvation gas flow (L/Hr) 400, mass range: 150 to IQOO Da.
LC HP 1100 HPLC from Agilent: solvent degasser, quaternary pump, heated column compartment and diode-array detector.
Column: Phenomenex Gemini C18, length (mm) 30, internal diameter (mm) 3, particle size (μm) 3, temperature (0C) 60, DAD wavelength range (nm): 200 to
500, solvent gradient: A = 0.05% v/v formic acid in water and B = 0.04% v/v formic acid in acetonitrile / methanol (4:1).
Time (min) A% B% Flow (ml/min)
0.0 95 5.0 1.7
2.0 0.0 100 1.7
2.8 0.0 100 1.7
2.9 95 5.0 1.7
Method B
MS ZMD Mass Spectrometer from Waters (single quadrupole mass spectrometer), ionization method: electrospray, polarity: positive ionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V) 3.00, source temperature (0C) 150, desolvation temperature (0C) 320, cone gas flow (L/Hr) 50, desolvation gas flow (L/Hr) 400, mass range: 150 to 800 Da.
LC Alliance 2795 LC HPLC from Waters: quaternary pump, heated column compartment and diode-array detector.
Column: Waters Atlantis dcl8, length (mm) 20, internal diameter (mm) 3, particle size (μm) 3, temperature (0C) 40, DAD wavelength range (nm): 200 to 500, solvent gradient: A = 0.1% v/v formic acid in water and B = 0.1% v/v formic acid in acetonitrile. Time (min) A% B% Flow (ml/min)
0.0 80 20 1.7
5.0 0.0 100 1.7
5.6 0.0 100 1.7
6.0 80 20 1.7
Method C
MS ZQ Mass Spectrometer from Waters (single quadrupole mass spectrometer), ionization method: electrospray, polarity: positive ionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V) 3.00, source temperature (0C) 100, desolvation temperature (0C) 200, cone gas flow (L/Hr) 200, desolvation gas flow (L/Hr) 250, mass range: 150 to 800 Da.
LC 1 lOOer Series HPLC from Agilent: quaternary pump, heated column compartment and diode-array detector.
Column: Waters Atlantis del 8, length (mm) 20, internal diameter (mm) 3, particle size (μm) 3, temperature (0C) 40, DAD wavelength range (nm): 200 to
500, solvent gradient: A = 0.1% v/v formic acid in water and B = 0.1% v/v formic acid in acetonitrile.
Time (min) A% B% Flow (ml/min)
0.0 90 10 1.7
5.5 0.0 100 1.7
5.8 0.0 100 1.7
5.9 90 10 1.7
Method D
MS ZMD Mass Spectrometer from Waters (single quadrupole mass spectrometer), ionization method: electrospray, polarity: positive ionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V) 3.00, source temperature (0C) 150, desolvation temperature (0C) 320, cone gas flow (L/Hr) 50, desolvation gas flow (L/Hr) 400, mass range: 150 to 800 Da.
LC Alliance 2795 LC HPLC from Waters: quaternary pump, heated column compartment and diode-array detector.
Column: Waters Atlantis del 8, length (mm) 20, internal diameter (mm) 3, particle size (μm) 3, temperature (0C) 40, DAD wavelength range (nm): 200 to
500, solvent gradient: A = 0.1% v/v formic acid in water and B = 0.1% v/v formic acid in acetonitrile.
Time (min) A% B% Flow (ml/min)
0.0 80 20 1.7
2.5 0.0 100 1.7
2.8 0.0 100 1.7
2.9 80 20 1.7
Method E
MS ZQ Mass Spectrometer from Waters (single quadrupole mass spectrometer), ionization method: electrospray, polarity: positive ionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V) 3.00, source temperature (0C) 100, desolvation temperature (0C) 200, cone gas flow (L/Hr) 200, desolvation gas flow (L/Hr) 250, mass range: 150 to 800 Da. LC 1 lOOer Series HPLC from Agilent: quaternary pump, heated column compartment and diode-array detector.
Column: Waters Atlantis del 8, lenj gth (mm) 20, internal diameter (mm) 3, particle size (μm) 3, temperature (° C) 40, DAD wavelength range (nm): 200 to
500, solvent gradient: A = 0.1% v/v formic acid in water and B = 0.1% v/v formic acid in acetonitrile.
Time (min) A% B% Flow (ml/min)
0.0 80 20 1.7
2.5 0.0 100 1.7
2.8 0.0 100 1.7
2.9 80 20 1.7
Example II : Preparation of 4-bromo-3-methyl-benzylamine
LiAIH,
To a solution of 4-bromo-3-methyl-benzonitrile (commercially available) (15 g) in diethyl ether (150 ml) under an argon atmosphere was added a solution of lithium aluminum hydride in diethyl ether (IM) (150 ml) at ambient temperature. The reaction mixture was stirred at 400C for 2 hours. Then the reaction mixture was cooled to 00C and quenched by successive addition of water (10.5 ml), aqueous sodium hydroxide (20% w/w) (7.5 ml) and water (37.5 ml). The phases were separated. The organic phase was filtered through a plug of silica gel and the filtrate concentrated to give 4-bromo-3-methyl-benzylamine (15.11 g) as a yellow oil. IH-NMR (400 MHz, CDCl3): 7.47 (d, IH), 7.19 (s, IH), 6.98 (d, IH), 3.80 (s, 2H), 2.39 (s, 3H) ppm.
Example 12: Preparation of Λ/-(4-bromo-3-methyl-benzyl)-formamide
To a solution of 4-bromo-3-methyl-benzylamine (15.11 g) (Example II) in ethyl formate (150 ml) was added triethylamine (1.5 ml) at ambient temperature. The reaction mixture was stirred at reflux for 16 hours. The reaction mixture was concentrated and the residue was triturated with diisopropyl ether / heptane (1 : 1) (100 ml) to give JV-(4-bromo-3- methyl-benzyl)-formamide (14.04 g) as a white solid. IH-NMR (400 MHz, CDCl3): 8.28 (s, IH), 7.49 (m, IH), 7.16 (s, IH), 6.97 (m, IH), 5.85 (s, IH), 4.42 (m, 2H), 2.39 (s, 3H) ppm. Example 13: Preparation of l-bromo-4-isocvanomethyl-2-methyl-benzene
To a solution of Λ/-(4-bromo-3-methyl-benzyl)-formamide (4.3 g) (Example 12) in dichloromethane (70 ml) was added a solution of phosphorus oxy chloride (2.8 g) in dichloromethane (15 ml) at 0-50C. The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured onto a mixture of ice and water (400 ml), and sodium hydrogen carbonate (saturated) (100 ml) and ethyl acetate (250 ml) were added. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and concentrated to give l-bromo-4-isocyanomethyl-2-methyl-benzene (4.52 g) as a brown oil. IH-NMR (400 MHz, CDCl3): 7.54 (m, IH), 7.22 (s, IH), 7.03 (m, IH), 4.57 (s, 2H), 2.42 (s, 3H) ppm.
Example 14: Preparation of 2-(4-bromo-3-methyl-phenyl)-4-(3,5-dichloro-phenyl)-4- trifluoromethyl-3,4-dihvdro-2H-pyrrole
A mixture of l,3-dichloro-5-(l-trifluoromethyl-vinyl)-benzene (8.03 g) (made as described in EP 1,731,512), l-bromo-4-isocyanomethyl-2-methyl-benzene (Example 13) (4.16 g) and copper(I) oxide (0.13 g) in toluene (50 ml) was stirred at 1100C for 16 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate / heptane) to give 2-(4-bromo-3-methyl-phenyl)-4-(3,5-dichloro- phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrole (2.39 g). 1Η-NMR (4OO MHz, CDCl3): 7.39-6.86 (m, 7H), 5.39-4.98 (m, IH), 3.24-2.77 (m, IH), 2.35 (m, 3H), 2.32-2.09 (m, IH) ppm. Example 15: Preparation of 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-
Pyrrol-2-yll-2-methyl-benzoic acid ethyl ester
To a solution of 2-(4-bromo-3-methyl-phenyl)-4-(3,5-dichloro-phenyl)-4- trifluoromethyl-3,4-dihydro-2H-pyrrole (Example 14) (7.0 g) in a mixture of ethanol (60 ml) and dimethylformamide (20 ml), was added dichloro 1 , r-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane adduct ("Pd(dppf)Cl2") (0.8 g) and sodium acetate (1.4 g) at ambient temperature. The reaction mixture was stirred in a pressure reactor in an atmosphere of carbon monoxide (6 bar) at 85°C for 16 hours. The reaction mixture was cooled to ambient temperature, the ethanol was evaporated and aqueous sodium hydrogen carbonate (saturated) (200 ml) and ethyl acetate (250 ml) were added. The phases were separated and the organic phase was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: gradient of 0-4% v/v methanol in dichloromethane) to give 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrol-2-yl]-2-methyl- benzoic acid ethyl ester (2.8 g). 1Η-NMR (CDCl3, 400 MHz): 8.04-7.06 (m, 7H), 5.46-5.06 (m, IH), 4.35 (m, 2H), 3.27-3.79 (m, IH), 2.59 (m, 3H), 2.38-2.10 (m, IH), 1.39 (m, 3H) ppm.
Example 16: Preparation of 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H- Pyrrol-2-yll-2-methyl-benzoic acid
To a solution of 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrol- 2-yl]-2-methyl-benzoic acid ethyl ester (Example 15) (2.8 g) in ethanol (40 ml) was added a solution of sodium hydroxide (0.51 g) in water (15 ml). The reaction mixture was stirred at reflux for 1 hour. After cooling to ambient temperature aqueous hydrochloric acid (IM) (20 ml), water (150 ml) and ethyl acetate (200 ml) was added. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was recrystallised from diisopropyl ether to give 4-[4-(3,5-dichloro-phenyl)-4- trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-benzoic acid (2.02 g) as a white solid. 1Η-NMR (de-DMSO, 400 MHz): 13.07 (s, IH), 7.91-7.58 (m, 6H), 4.85 (d, IH), 4.44 (d, IH), 3.92-3.35 (m, 2H), 2.58 (s, 3H) ppm.
Example 17: Preparation of 2-methyl-N-trimethylsilanylmethyl-terephthalamic acid methyl ester
To a solution of 2-methyl-terephthalic acid 1-methylester (preparation see WO 2000/021920) (1.43 g) in dichloromethane (10 ml) was added N-(-3-dimethylaminopropyl)-N"- ethylcarbodiimid hydrochloride (1.84 g), N,N-dimethylaminopyridine (0.41 g) and trimethylsilylmethylamine (1 ml). The reaction mixture was stirred at ambient temperature, for 2 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate / heptanes 1 :3) to give 2-methyl-N- trimethylsilanylmethyl-terephthalamic acid methyl ester (1.85 g). IH-NMR (400 MHz, CDCl3): 7.72 (d, IH), 7.45 (s, IH), 7.40 (d, IH), 5.85 (s, IH), 3.78 (s, 3H), 2.84 (d, 2H), 2.49 (s, 3H), 0.00 (s, 9H) ppm. 2-Methyl-N-trimethylsilanylmethyl-terephthalamic acid tert-butyl ester was obtained using a similar procedure. IH-NMR (400 MHz, CDCl3): 7.82 (d, IH), 7.48 (s, IH), 7.39 (d, IH), 5.70 (s, IH), 2.82 (d, 2H), 2.48 (s, 3H), 1.48 (s, 9H), 0.00 (s, 9H) ppm.
Example 18: Preparation of 2-methyl-4-(trimethylsilanylmethyl-thiocarbamoyl)-benzoic acid methyl ester
To a solution of 2-methyl-N-trimethylsilanylmethyl-terephthalamic acid methyl ester (Example 17) (1.83 g) in toluene (50 ml) was added 2,4-bis(4-methoxyphenyl)-l,3,2,4- dithiadiphosphetane 2,4-disulfide (Lawesson reagent) (2.65 g). The reaction mixture was stirred at ambient temperature for 30 minutes and then at 110 0C for 1.5 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate / heptanes 1 :5) to give 2-methyl-4-(trimethylsilanylmethyl-thiocarbamoyl)- benzoic acid methyl ester (1.85 g). IH-NMR (400 MHz, CDCl3): 7.75-7.20 (m, 3H), 3.70 (s, 3H), 3.35 (m, 2H), 2.45 (s, 3H), 0.00 (s, 9H) ppm.
2-Methyl-4-(trimethylsilanylmethyl-thiocarbamoyl)-benzoic acid tert-butyl ester was obtained using a similar procedure. 1H-NMR (400 MHz, CDCl3): 7.62 (d, IH), 7.40 (s, br, IH), 7.35 (s, IH), 7.25 (d, IH), 3.35 (d, 2H), 2.40 (s, 3H), 1.40 (s, 9H), 0.00 (s, 9H) ppm.
Example 19: Preparation of 2-methyl-4-(methylsulfanyl-trimethylsilanylmethylimino"|- methvD-benzoic acid methyl ester
To a solution of 2-methyl-4-(trimethylsilanylmethyl-thiocarbamoyl)-benzoic acid methyl ester (Example 18) (200 mg) in acetonitrile (4 ml) was added potassium carbonate (140 mg) and methyl iodide (120 mg). The reaction mixture was stirred at ambient temperature for 20 hours. Water and ethyl acetate was added to the reaction mixture. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue purified by chromatography on silica gel (eluent: ethyl acetate / heptanes 1 :5) to give 2-methyl-4-(methylsulfanyl-trimethylsilanylmethylimino]-methyl)-benzoic acid methyl ester (124 mg). IH-NMR (400 MHz, CDCl3): 7.82-7.20 (m, 3H), 3.80 (s, 3H), 3.50 (m, 2H), 2.50 (s, 3H), 1.92 (s, 3H), 0.00 (s, 9H) ppm.
2-Methyl-4- {methylsulfanyl-[(E)-trimethylsilanylmethylimino]-methyl} -benzoic acid tert- butyl ester was obtained using a similar procedure. IH-NMR (400 MHz, CDCl3): 7.62 (d, IH), 7.23-7.20 (m, 2H), 3.03 (m, 2H), 2.48 (s, 3H), 1.95 (s, 3H), 1.45 (s, 9H), 0.00 (s, 9H) ppm. Example IIP: Preparation of 4-[4-(3,5-Bis-trifluoromethyl-phenyl)-4-trifluoromethyl-3,4- dihydro-2H-pyrrol-2-yll-2-methyl-benzoic acid methyl ester
To a solution of 2-methyl-4-(methylsulfanyl-trimethylsilanylmethylimino]-methyl)-benzoic acid methyl ester (Example 19) (135 mg) and l,3-bis-trifluoromethyl-5-(l-trifluoromethyl- vinyl)-benzene (see WO 2007125984) (179 mg) in THF (5 ml) was added at 5 0C tetrabutylammonium fluoride (TBAF) (0.11 ml, IM in THF). The reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was filtered over silica and concentrated. The residue was purified by preparative HPLC to give 4-[4-(3,5-bis- trifluoromethyl-phenyl)-4-trifluoromethyl-3 ,4-dihydro-2H-pyrrol-2-yl] -2-methyl-benzoic acid methyl ester (124 mg). 1H-NMR (400 MHz, CDCl3): 8.60-7.70 (m, 6H), 5.03 (d, IH), 4.52 (d, IH), 3.98-3.90 (m, 4H), 3.55-3.40 (m, IH), 2.68 (s, 3H) ppm. 2-Methyl-4-[4-(3,4,5-trichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]- benzoic acid methyl ester was obtained using a similar procedure. 1H-NMR (400 MHz, CDCl3): 8.0-7.42 (m, 5H), 4.90 (d, IH), 4.45 (d, IH), 3.93 (s, 3H), 3.80 (d, IH), 3.45 (d, IH), 2.65 (s, 3H) ppm.
Example 111 : Preparation of 4-[4-(3,5-Bis-trifluoromethyl-phenyl)-4-trifluoromethyl-4,5- dihvdro-3H-pyrrol-2-yl"|-2-methyl-benzoic acid
To a solution of 2-methyl-4-(methylsulfanyl-trimethylsilanylmethylimino]-methyl)-benzoic acid methyl ester (Example 110) (115 mg) in THF (4 ml) and water (2 ml) was added Lithium hydroxide mo no hydrate (24 mg). The reaction mixture was stirred at 50 0C for 16 hours. The reaction mixture was cooled to ambient temperature and diluted with water, acidified by addition of aqueous hydrochloric acid (IM) and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to give 4-[4-(3,5-Bis-trifluoromethyl-phenyl)-4-trifluoromethyl-4,5-dihydro-
3H-pyrrol-2-yl]-2-methyl-benzoic acid (109 mg). 1H-NMR (400 MHz, CDCl3): 8.15-7.72 (m, 6H), 5.05 (d, IH), 4.55 (d, IH), 3.95 (d, IH), 3.55 (d, IH), 2.70 (s, 3H) ppm. 2-Methyl-4-[4-(3,4,5-trichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]- benzoic acid was obtained using a similar procedure. 1H-NMR (400 MHz, CDCl3): 7.95-7.55 (m, 5H), 4.76 (d, IH), 4.30 (d, IH), 3.65 (d, IH), 3.30 (d, IH), 2.55 (s, 3H) ppm.
Example 112: Preparation of 4-Bromo-3-chloro-N-trimethylsilanylmethyl-benzamide
To a solution of 4-bromo-3-chloro-benzoic acid (commercially available) (5.0 g) in dichloromethane (30 ml) was added N-(-3-dimethylaminopropyl)-N"-ethylcarbodiimid hydrochloride (5.29 g), N,N-dimethylaminopyridine (1.19 g) and trimethylsilylmethylamine (2.85 ml). The reaction mixture was stirred at ambient temperature for 5 hours. Water and dichloromethane was added to the reaction mixture. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and filtered through silica gel. The reaction mixture was concentrated to give 4-bromo-3-chloro-N- trimethylsilanylmethyl-benzamide (4.87 g). IH-NMR (400 MHz, CDCl3): 7.68 (d, IH), 7.55 (s, IH), 7.33 (d, IH), 5.85 (s, IH), 2.84 (d, 2H), 0.00 (s, 9H) ppm.
Example 113: Preparation of 4-Bromo-3-chloro-N-trimethylsilanylmethylthiobenzamide
Lawesson reagent To a solution of 4-bromo-3-chloro-N-trimethylsilanylmethyl-benzamide (Example 112) (4.6 g) in toluene (150 ml) was added 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane 2,4- disulfide (Lawesson reagent) (5.8 g). The reaction mixture was stirred at ambient temperature for 30 minutes and then at 110 0C for 1.5 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate / heptanes 1 :5) to give 4-bromo-3-chloro-N-trimethylsilanylmethylthiobenzamide (4.64 g). IH-NMR (400 MHz, CDCl3): IH-NMR (400 MHz, CDCl3): 7.60 (d, IH), 7.45 (s, IH), 7. 30 (s, IH), 7.25 (d, IH), 3.33 (d, 2H), 0.00 (s, 9H) ppm.
Example 114: Preparation of 4-Bromo-3-chloro-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester
To a solution of 4-bromo-3-chloro-N-trimethylsilanylmethylthiobenzamide (Example 113) (4.43 g) in butanone (80 ml) was added potassium carbonate (2.73 g) and methyl iodide (1.02 ml). The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate / heptanes 1 :5) to give of 4-bromo-3-chloro-N-trimethylsilanylmethyl- thiobenzimidic acid methyl ester (2.56 g). IH-NMR (400 MHz, CDCl3): 7.55-7.15 (m, 3H), 3.55 (s, 2H), 1.98 (s, 3H), 0.00 (s, 9H) ppm.
Example 115: Preparation of 5-(4-Bromo-3-chloro-phenyl)-3-(3,5-dichloro-phenyl)-3- methyl-3 ,4-dihydro-2H-pyrrole
To a solution of 4-bromo-3-chloro-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (Example 114) (1.83 g) and l,3-dichloro-5-(l-trifluoromethyl-vinyl)-benzene (see WO 2007125984) (1.38 g) in THF (25 ml) was added at -5 0C tetrabutylammonium fluoride trihydrate (TBAF) (0.41 g) dissolved in THF (15 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture concentrated and the residue was purified by chromatography on silica gel (eluent: ethyl acetate / heptanes 1 :6) to give 5-(4-bromo-3-chloro-phenyl)-3-(3,5-dichloro-phenyl)-3-methyl-3,4-dihydro-2H-pyrrole (2.50 g). 1H-NMR (400 MHz, CDCl3): 7.95-7.25 (m, 6H), 4.88 (d, IH), 4.42 (d, IH), 3.75 (d, IH), 3.40 (d, IH) ppm.
Example 116: Preparation of 2-Chloro-4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5- dihydro-3H-pyrrol-2-yll-benzoic acid butyl ester
Cataxium A (68 mg) and palladium acetate (13 mg) were dissolved in butanol (30 ml) under an argon atmosphere. Tetramethylene diamine (0.29 ml) and 5-(4-bromo-3-chloro-phenyl)-3- (3,5-dichloro-phenyl)-3-methyl-3,4-dihydro-2H-pyrrole (1.11 g) were added at ambient temperature. The reaction mixture was stirred in a pressure reactor in an atmosphere of carbon monoxide (6 bar) at 115°C for 16 hours. The reaction mixture was cooled to ambient temperature, filtered and ethyl acetate (250 ml) was added. The mixture was washed with water (50 ml), brine (50 ml), dried over anhydrous sodium sulphate, filtered over a small layer of silica and concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / heptanes 1 :4) to give 2-chloro-4-[4-(3,5-dichloro-phenyl)-4- trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-benzoic acid butyl ester (0.49 g). 1H-NMR (400 MHz, CDCl3): 7.95-7.25 (m, 6H), 4.92 (d, IH), 4.45 (d, IH), 4.37 (t, 2H), 3.78 (d, IH), 3.45 (d, IH), 1.75 (m, 2H), 1.50 (m, 2H), 0.95 (t, 3H) ppm. Example 117: Preparation of 2-Chloro-4-[4-(3,5-dichloro-phenyl)-4-methyl-4,5-dihydro-3H-
Pyrrol-2-vH-benzoic acid
solution of 2-chloro-4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrro 1-2- yl]-benzoic acid butyl ester (Example 116) (0.48 g) in THF (16 ml) and water (8 ml) was added lithium hydroxide mono hydrate (103 mg). The reaction mixture was stirred at 50 0C for 20 hours. The reaction mixture was cooled to ambient temperature and diluted with water, acidified by addition of aqueous hydrochloric acid (IM) and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to give 2-chloro-4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5- dihydro-3H-pyrrol-2-yl]-benzoic acid (459 mg). 1H-NMR (400 MHz, CDCl3): 8.15-7.40 (m, 6H), 4.95 (d, IH), 4.30 (d, IH), 3.85 (d, IH), 3.35 (d, IH) ppm.
Example 118: Preparation of 2-Methyl-4-{methylsulfanyl-[(Z)-trimethylsilanyl methyliminol methyl) -benzoic acid
To a solution of 2-methyl-4-{methylsulfanyl-[(E)-trimethylsilanylmethylimino]-methyl}- benzoic acid tert-butyl ester (see Example 19) (118 mg) in dichloromethane (15 ml) was added trifluoroacetic acid (0.22 ml). The reaction mixture was stirred at ambient temperature for 20 hours. Further trifluoroacetic acid (0.11 ml) was added and the mixture was stirred for another 3 hours at ambient temperature. Water was added and the mixture was extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to give 2-methyl-4-{methylsulfanyl-[(Z)- trimethylsilanyl methylimino]methyl} -benzoic acid which was used without further purification in the subsequent step. LC-MS (Method A): RT (min): 1.32; [M+H]+ :296
Example 119: Preparation of 3-Methyl-4-(thietan-3-ylcarbamoyl)-N-trimethylsilanylmethyl- thiobenzimidic acid methyl ester
To a solution of 2-methyl-4-{methylsulfanyl-[(Z)-trimethylsilanyl methylimino]methyl}- benzoic acid (Example 118) (107 mg) in dichloromethane (6 ml) was added thietan-3- ylamine (88 mg), Hϋnigs base (0.248 ml) and 2-bromo-l-ethyl-pyridinium tetrafluoroborate (169 mg). The reaction mixture was stirred at ambient temperature for 2 hours. Water was added and the mixture was extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / heptanes 1 :3) to give 3- methyl-4-(thietan-3 -ylcarbamoyl)-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (16 mg). IH-NMR (400 MHz, CDCl3): 7.40-7.20 (m, 3H), 6.20 (d, IH); 5.30 (m, IH), 3.55 (s, 2H), 3.35 (m, 2H), 3.25 (m, 2H), 2.35 (s, 3H), 1.95 (s, 3H), 0.00 (s, 9H) ppm. LC-MS (Methode A): RT (min): 1.33; [M+H]+ :367
Example 120: Preparation of 4-[4-(3,5-Dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H- pyrrol-2-yl] -2-methyl-N-thietan-3 -yl-benzamide
To a solution of 3-methyl-4-(thietan-3-ylcarbamoyl)-N-trimethylsilanylmethyl- thiobenzimidic acid methyl ester (Example 119) (16 mg) and l,3-dichloro-5-(l- trifluoromethyl-vinyl)-benzene (see WO 2007/125984) (12 mg) in THF (2 ml) was added at -5 0C tetrabutylammonium fluoride trihydrate (TBAF) (0.41 g) dissolved in THF (1.5 ml). The reaction mixture was stirred at ambient temperature for 16 hours. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate / heptanes 1 :2) to give 4-[4-(3,5-dichloro- phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-N-thietan-3-yl-benzamide (20 mg). 1H-NMR (400 MHz, CDCl3): 7.75-7.25 (m, 6H), 6.30 (s, IH), 5.45 (m, IH), 4.90 (d, IH), 4.45 (d, IH), 3.82 (d, IH), 3.55-3.38 (m, 5H), 2.48 (s, 3H) ppm.
Example 121 : Preparation of 4-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl- butyryll -2-methyl-N-thietan-3 - yl-benzamide
To a solution of 4-[(Z)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-N- thietan-3-yl-benzamide (general preparation described in WO 2009/080250) (100 mg) in DMF (1 ml) nitromethane (0.011 ml) and IM sodium hydroxide (0.211 ml) was added at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 hour. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by prep. HPLC to give give 4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro- 3-nitromethyl-butyryl]-2-methyl-N-thietan-3-yl-benzamide (78 mg). 1H-NMR (400 MHz, CDCl3): 7.85-7.20 (m, 6H), 6.25 (d, IH), 5.62 (d, IH), 5.45 (m, 2H), 4.15 (d, IH), 4.00 (d, IH), 3.58-3.38 (m, 4H), 2.55 (s, 3H) ppm.
Example 122: Preparation of 4-[4-(3,5-Dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H- pyrrol-2-yl] -2-methyl-N-thietan-3 -yl-benzamide
To a solution of 4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl- N-thietan-3 -yl-benzamide (Example 121) (78 mg) in DMF (1.5 ml) zinc powder (48 mg) was added at ambient temperature. The reaction mixture was heated to 80 0C and concentrated hydrochloric acid (0.3 ml) was added drop-wise. The reaction mixture was stirred at 80 0C for 4 hours. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by prep. HPLC to give give 4-[4-(3,5-dichloro- phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-N-thietan-3-yl-benzamide (12 mg). 1H-NMR (400 MHz, CDCl3): 7.75-7.25 (m, 6H), 6.35 (s, IH), 5.45 (m, IH), 4.90 (d, IH), 4.45 (d, IH), 3.82 (d, IH), 3.55-3.38 (m, 5H), 2.48 (s, 3H) ppm.
Example Pl : Method for preparing the compounds of the invention from a carboxylic acid
To a solution of the appropriate carboxylic acid (30 μmol), for example 4-[4-(3,5-dichloro- phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-benzoic acid (Example 16) in the case of Compound No. Al of Table A, in dimethylacetamide (0.4 ml) was added successively a solution of an amine of formula HNR1R2 (36 μmol), for example 1,1-dioxo- thietan-3-ylamine (preparation described in, for example, WO 2007/080131) in the case of Compound No. Al of Table A, in dimethylacetamide (0.145 ml), diisopropylethylamine (Hunig's Base) (0.02 ml, 100 μmol), and a solution of bis(2-oxo-3-oxazolidinyl)phosphonic chloride ("BOP-Cl") (15.3 mg) in dimethylacetamide (0.2 ml). The reaction mixture was stirred at 1000C for 16 hours. Then the reaction mixture was diluted with acetonitrile (0.6 ml) and a sample was used for LC-MS analysis. The remaining mixture was further diluted with acetonitrile / dimethylformamide (4:1) (0.8 ml) and purified by HPLC. This method was used to prepare a number of compounds (Compound Nos. Al to A4 of Table A) in parallel. Compounds Nos. A5 to AlO, Bl to B4 and Cl to C were obtained using a similar procedure.
Table A:
Table A provides compounds of formula (Ia) where G is oxygen, R3 is trifluoromethyl, R4 is
3,5-dichloro-phenyl-, R5 is methyl, and R1 and R2 have the values listed in the table below.
Table B:
Table B provides compounds of formula (Ia) where G is oxygen, R1 is Hydrogen, R5 is methyl, R3 is trifluoromethyl, and R2 and R4 have the values listed in the table below.
Table C:
Table C provides compounds of formula (Ia) where G is oxygen, R1 is Hydrogen, R4 is 3,5- dichloro -phenyl-, and R2, R3 and R5 have the values listed in the table below.
Table D:
Table D provides compounds of formula (Ib) where G is oxygen, R3 is trifluoromethyl, R4 is
3,5-dichloro-phenyl- and R1 and R2 have the values listed in the table below.
Biological examples
This Example illustrates the insecticidal and acaricidal properties of compounds of formula
(I). The tests were performed as follows:
Spodoptera littoralis (Egyptian cotton leafworm):
Cotton leaf discs were placed on agar in a 24-well microtiter plate and sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs were infested with 5 Ll larvae. The samples were checked for mortality, feeding behavior, and growth regulation 3 days after treatment (DAT). The following compound gave at least 80% control of Spodoptera littoralis: Al, A2, A3, A4, A5, A6, A7, A8, A9, AlO, Bl, B2, B3, B4, B5, B6, Cl, C2, C3, Dl, D2, D3
Heliothis virescens (Tobacco budworm):
Eggs (0-24 h old) were placed in 24-well microtiter plate on artificial diet and treated with test solutions at an application rate of 200 ppm (concentration in well 18 ppm) by pipetting.
After an incubation period of 4 days, samples were checked for egg mortality, larval mortality, and growth regulation.
The following compound gave at least 80% control of Heliothis virescens: Al, A2, A3, A4,
A5, A6, A7, A8, A9, AlO, Bl, B2, B3, B4, B5, B6, Cl, C2, C3, Dl, D2, D3. Plutella xylostella (Diamond back moth):
24-well microtiter plate (MTP) with artificial diet was treated with test solutions at an application rate of 200 ppm (concentration in well 18 ppm) by pipetting. After drying, the MTP's were infested with L2 larvae (7-12 per well). After an incubation period of 6 days, samples were checked for larval mortality and growth regulation.
The following compound gave at least 80% control oϊPlutella xylostella: Al, A2, A3, A4 ,A5, A6, A7, A8, A9, AlO, Bl, B2, B3, B4, B5, B6, Cl, C2, C3, Dl, D2, D3.
Diabrotica balteata (Corn root worm): A 24-well microtiter plate (MTP) with artificial diet was treated with test solutions at an application rate of 200 ppm (concentration in well 18 ppm) by pipetting. After drying, the
MTP's were infested with L2 larvae (6-10 per well). After an incubation period of 5 days, samples were checked for larval mortality and growth regulation.
The following compound gave at least 80% control of Diabrotica balteata: Al, A2, A3, A4 , A5, A6, A7, A8, A9, AlO, Bl, B2, B3, B4, B5, B6, Cl, C2, C3, Dl, D2, D3.
Thrips tabaci (Onion thrips):
Sunflower leaf discs were placed on agar in a 24-well microtiter plate and sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs were infested with an aphid population of mixed ages. After an incubation period of 7 days, samples were checked for mortality.
The following compounds gave at least 80% control of Thrips tabaci: Al, A2, A3, A4, A5, A6, A7, A8, A9, AlO, Bl, B2, B3, B4, B5, B6, Cl, C2, C3, Dl, D2, D3.
Tetranychus urticae (Two-spotted spider mite):
Bean leaf discs on agar in 24-well microtiter plates were sprayed with test solutions at an application rate of 200 ppm. After drying, the leaf discs are infested with mite populations of mixed ages. 8 days later, discs are checked for egg mortality, larval mortality, and adult mortality. The following compound gave at least 80% control of Tetranychus urticae: Al, A2, A3, A4 ,A5, A6, A7, A8, A9, AlO, Bl, B2, B3, B4, B5, B6, Cl, C2, C3, Dl, D2, D3.

Claims

1. A compound of formula (I)
where
A1, A2, A3 and A4 are independently of each other C-H, C-R5 or nitrogen;
G is oxygen or sulfur;
R1 is hydrogen, Ci-Csalkyl, Ci-Csalkoxy-, Ci-Csalkylcarbonyl- or Ci-Csalkoxycarbonyl-;
R2 is a group of formula (II)
Y^γ2
>Vf (H)
R where
L is a single bond or Ci-Cβalkylene; and
Y1, Y2 and Y3 are independently of another CR8R9, C=O, C=N-OR10, N-R10, S, SO, SO2,
S=N-R10 or SO=N-R10, provided that at least one of Y1, Y2 or Y3 is not CR8R9, C=O or C=N-
OR10; R3 is Ci-Cghaloalkyl;
R4 is aryl or aryl substituted by one to five R7, or heteroaryl or heteroaryl substituted by one to five R7; each R5 is independently halogen, cyano, nitro, Ci-Csalkyl, Ci-Cshaloalkyl, Ci-Csalkenyl,
Ci-Cshaloalkenyl, Ci-Csalkynyl, Ci-Cshaloalkynyl, C3-Ciocycloalkyl, Ci-Csalkoxy-, C1- Cshaloalkoxy-, d-Cgalkylthio-, Ci-C8haloalkylthio-, d-Cgalkylsulfϊnyl-, Ci-Cshaloalkyl- sulfinyl-, Ci-Csalkylsulfonyl- or Ci-Cshaloalkylsulfonyl-, or two R5 on adjacent carbon atoms together form a -CH=CH-CH=CH- bridge;
R6 is hydrogen or d-Cgalkyl; each R7 is independently halogen, cyano, nitro, d-Cgalkyl, d-Cghaloalkyl, C2-Cgalkenyl, C2-Cghaloalkenyl, C2-Cgalkynyl, C2-Cghaloalkynyl, hydroxy, Ci-Csalkoxy-, C1-
Cshaloalkoxy-, mercapto, d-Cgalkylthio-, Ci-Cshaloalkylthio-, d-Cgalkylsulfinyl-, C1-
Cshaloalkylsulfinyl-, Ci-Csalkylsulfonyl-, Ci-Cshaloalkylsulfonyl-, Ci-Csalkylcarbonyl-, Ci- Csalkoxycarbonyl-, aryl or aryl substituted by one to five R11, or heterocyclyl or heterocyclyl substituted by one to five R11; each R8 and R9 is independently hydrogen, halogen, Ci-Csalkyl or Ci-Cshaloalkyl; each R10 is independently hydrogen, cyano, Ci-Csalkyl, Ci-Cshaloalkyl, Ci-Csalkylcarbonyl- , Ci-Cshaloalkylcarbonyl-, Ci-Csalkoxycarbonyl-, Ci-Cshaloalkoxycarbonyl-, Ci-Csalkyl- sulfonyl-, Ci-Cshaloalkylsulfonyl-, aryl-Ci-C4alkylene- or aryl-Ci-C4alkylene- where the aryl moiety is substituted by one to three R12, or or heteroaryl-Ci-
C4alkylene- where the heteroaryl moiety is substituted by one to three R12; each R11 and R12 is independently halogen, cyano, nitro, d-Cgalkyl, Ci-C8haloalkyl, C1- C8alkoxy-, Ci-Cshaloalkoxy- or d-C8alkoxycarbonyl-; or a salt or JV-oxide thereof.
2. A compound according to claim 1 where A1 is C-R5, A2 is C-H, A3 is C-H or nitrogen and A4 is C-H or nitrogen;
3. A compound according to claim 1 or claim 2 where G is oxygen.
4. A compound according to any one of claims 1 to 3 where R1 is hydrogen, methyl, ethyl, methylcarbonyl-, or methoxycarbonyl-.
5. A compound according to any one of claims 1 to 4 where R2 is a group of formula
(lie)
where
R , 1133 is Ci-Cgalkyl, m is 0, 1, 2, 3, 4, or 5, and
Y2 is S, SO, SO2, S=N-R10, SO=N-R10 or C=N-OR10.
6. A compound according to any one of claims 1 to 5 where R is chlorodifluoromethyl or trifluoromethyl.
7. A compound according to any one of claims 1 to 6 where R4 is phenyl or phenyl substituted by one to five R7.
8. A compound according to claim 1 wherein
A1, A2, A3 and A4 are independently of each other C-H or C-R5;
G is oxygen;
R1 is hydrogen, methyl or ethyl;
R2 is a group of formula (lib)
where
L is a single bond, methylene ethylene or propylene; one of Y1 and Y2 is S, SO, SO2, S=N-R10, SO=N-R10 or C=N-OR10 and the other is
CH9
R3 is chlorodifluoromethyl or trifluoromethyl;
R4 is 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-, 3,4-dichloro-phenyl-, 3,4,5-trichloro-phenyl- or 3-trifluoromethyl-phenyl-; each R5 is independently bromo, chloro, fluoro, methyl, trifluoromethyl or vinyl, or two R5 on adjacent carbon atoms together form a -CH=CH-CH=CH- bridge; each R10 is independently methyl or hydrogen; R13 is hydrogen or d-Cgalkyl.
9. A compound according to claim 1 wherein A1 , A2, A3 and A4 are independently of each other C-H or C-R5;
G is oxygen; R1 is hydrogen; R2 is a group of formula (lie)
where m is 0, 1, 2, 3, 4, or 5, and
Y2 is S, SO, SO2, or C=N-OR10;
R3 is chlorodifluoromethyl or trifluoromethyl;
R4 is 3,5-dibromo-phenyl-, 3,5-dichloro-phenyl-, 3,5-bis-(trifluoromethyl)-phenyl-, 3,4-dichloro-phenyl-, 3,4,5-trichloro-phenyl- or 3-trifluoromethyl-phenyl-; each R5 is independently bromo, chloro, fluoro, methyl, trifluoromethyl or vinyl, or two R5 on adjacent carbon atoms together form a -CH=CH-CH=CH- bridge; each R10 is independently methyl or hydrogen; R13 is methyl.
10. A compound of formula (IA)
wherein
A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) in any one of claims 1 to 9; G is oxygen; and R is Ci-Cβalkoxy; or
a compound of formula (VA)
wherein
A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) in any one of claims 1 to 9;
R is Ci-Cβalkoxy; and XA is a halogen atom; or
a compound of formula (XIA)
(XIA) wherein
A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) in any one of claims 1 to 9; each R is independently Ci-Cβalkoxy;
G is oxygen; and
XA is a halogen atom; or
a compound of formula (XVII)
wherein
A1, A2, A3, A4, R1 and R2 are as defined for a compound of formula (I) in any one of claims 1 to 9;
R1', R2 and R3' are each independently Ci-Cs alkyl, Ci-Cs haloalkyl, phenyl or phenyl optionally substituted with one to five groups independently selected from halogen and C1-
C8 alkyl; and
R4' is Ci-C8 alkyl or Ci-C8 haloalkyl; or
a compound of formula (XX)
wherein
A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) in any one of claims 1 to 9; or
a compound of formula (XXIV) wherein
A 11, A Λ 2z, A Λ 33, A A 44, r R> 33 and R4 are as defined for a compound of formula (I) in any one of claims 1 to 9; and
XA is a halogen atom; or
a compound of formula (XXVI)
wherein
A1, A2, A3, A4, R1, R2, R3 and R4 are as defined for a compound of formula (I) in any one of claims 1 to 9; or
a compound of formula (XXVII)
(XXVII) wherein
A1, A2, A3, A4, R3 and R4 are as defined for a compound of formula (I) in any one of claims 1 to 9; and
XA is a halogen atom.
11. A method of controlling insects, acarines, nematodes or molluscs which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I) as defined in any one of claims 1 to 9.
12. An insecticidal, acaricidal, nematicidal or molluscicidal composition comprising an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound of formula (I) as defined in any one of claims 1 to 9.
13. An insecticidal, acaricidal, nematicidal or molluscicidal composition according to claim 12 comprising an additional compound having biological activity.
14. A method of treatment of insect pests in or on animals, comprising administering an effective amount of a compound as defined in any one of claims 1 to 9, or a composition comprising said compound, to an animal.
15. A compound according to any one of claims 1 to 9, or a composition comprising said compound, for use in treatment of insect pests in or on animals.
EP10726052.3A 2009-06-22 2010-06-11 Insecticidal compounds Active EP2445906B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP10726052.3A EP2445906B1 (en) 2009-06-22 2010-06-11 Insecticidal compounds

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB0910767A GB0910767D0 (en) 2009-06-22 2009-06-22 Insecticidal compounds
GB0910768A GB0910768D0 (en) 2009-06-22 2009-06-22 Insecticidal compounds
PCT/EP2009/059563 WO2010020522A1 (en) 2008-08-22 2009-07-24 Insecticidal compounds
EP10153810 2010-02-17
PCT/EP2010/058207 WO2010149506A1 (en) 2009-06-22 2010-06-11 Insecticidal compounds
EP10726052.3A EP2445906B1 (en) 2009-06-22 2010-06-11 Insecticidal compounds

Publications (2)

Publication Number Publication Date
EP2445906A1 true EP2445906A1 (en) 2012-05-02
EP2445906B1 EP2445906B1 (en) 2014-07-23

Family

ID=43386046

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10726052.3A Active EP2445906B1 (en) 2009-06-22 2010-06-11 Insecticidal compounds

Country Status (22)

Country Link
US (4) US8946447B2 (en)
EP (1) EP2445906B1 (en)
JP (1) JP5684802B2 (en)
KR (1) KR20120089626A (en)
CN (1) CN102803257B (en)
AR (1) AR077143A1 (en)
AU (1) AU2010264888B2 (en)
BR (1) BRPI1015931A2 (en)
CA (1) CA2764422A1 (en)
CO (1) CO6480914A2 (en)
CU (1) CU20110237A7 (en)
DO (1) DOP2011000400A (en)
EA (1) EA020755B1 (en)
ES (1) ES2502340T3 (en)
HK (1) HK1163694A1 (en)
MA (1) MA33372B1 (en)
MX (1) MX2011013448A (en)
NI (1) NI201100220A (en)
TW (1) TW201100013A (en)
UY (1) UY32727A (en)
WO (1) WO2010149506A1 (en)
ZA (1) ZA201109217B (en)

Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ590755A (en) 2008-08-22 2012-11-30 Syngenta Participations Ag Insecticidal compounds
CN102131804B (en) 2008-08-22 2014-12-03 先正达参股股份有限公司 Insecticidal compounds
US8686014B2 (en) 2008-09-04 2014-04-01 Syngenta Limited Insecticidal compounds
TWI487486B (en) 2009-12-01 2015-06-11 Syngenta Participations Ag Insecticidal compounds based on isoxazoline derivatives
JP2011219431A (en) 2010-04-13 2011-11-04 Bayer Cropscience Ag New aryl nitroalkane derivative
TW201211057A (en) * 2010-06-11 2012-03-16 Syngenta Participations Ag Process for the preparation of dihydropyrrole derivatives
JP2012017289A (en) * 2010-07-08 2012-01-26 Bayer Cropscience Ag Pesticidal pyrroline derivative
JP2012062267A (en) * 2010-09-15 2012-03-29 Bayer Cropscience Ag Pesticidal pyrroline n-oxide derivative
JP2014028758A (en) 2010-11-19 2014-02-13 Nissan Chem Ind Ltd Agent for controlling parasite and sanitary insect pest
UY33887A (en) 2011-02-03 2012-09-28 Syngenta Ltd PEST CONTROL METHODS IN SOYA
WO2012126881A1 (en) * 2011-03-22 2012-09-27 Syngenta Participations Ag Insecticidal compounds
AR086587A1 (en) 2011-05-31 2014-01-08 Syngenta Participations Ag INSECTICIDE COMPOUNDS
WO2013026939A1 (en) 2011-08-25 2013-02-28 Syngenta Participations Ag Methods for the control of termites and ants
WO2013026929A1 (en) 2011-08-25 2013-02-28 Syngenta Participations Ag Dihydropyrrole derivatives as insecticidal compounds
AR091513A1 (en) * 2012-06-21 2015-02-11 Syngenta Participations Ag SOIL PEST CONTROL METHODS
WO2013190050A1 (en) * 2012-06-21 2013-12-27 Syngenta Participations Ag Methods of controlling insects
BR112015001908A2 (en) 2012-07-31 2017-07-04 Syngenta Participations Ag soybean pest control methods
BR112015001979A2 (en) 2012-08-03 2017-07-04 Syngenta Participations Ag soybean pest control methods
BR112015001931A2 (en) 2012-08-03 2017-07-04 Syngenta Participations Ag soybean pest control methods
WO2014019951A1 (en) 2012-08-03 2014-02-06 Syngenta Participations Ag Methods of controlling insects
JP6238987B2 (en) 2012-08-24 2017-11-29 シンジェンタ パーティシペーションズ アーゲー How to control insects
US9661850B2 (en) 2012-08-24 2017-05-30 Syngenta Participations Ag Methods of soil pest control
AU2013305089B2 (en) 2012-08-24 2016-11-10 Syngenta Participations Ag Methods of controlling insects
EP2948439B1 (en) 2013-01-23 2020-06-03 Syngenta Participations AG Pyrazoline derivatives as insecticidal compounds
PE20161068A1 (en) * 2014-02-26 2016-10-21 Basf Se AZOLINE COMPOUNDS
EP3237380B1 (en) 2014-12-22 2019-04-03 Basf Se Azoline compounds substituted by a carbocyclic condensed ring system
WO2016102482A1 (en) * 2014-12-22 2016-06-30 Basf Se Azoline compounds substituted by a condensed ring system
US11213032B2 (en) 2017-03-23 2022-01-04 Syngenta Participations Ag Insecticidal compounds
WO2018172477A1 (en) 2017-03-23 2018-09-27 Syngenta Participations Ag Insecticidal compounds
WO2019243263A1 (en) 2018-06-19 2019-12-26 Syngenta Participations Ag Insecticidal compounds
US20220048876A1 (en) 2018-09-26 2022-02-17 Syngenta Participations Ag Insecticidal compounds
US11440861B2 (en) 2018-12-04 2022-09-13 Basf Se Process for preparation of 5-bromo-1,3-dichloro-2-fluoro-benzene

Family Cites Families (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6331640B1 (en) 1998-10-13 2001-12-18 Hoffmann-La Roche Inc. Diaminopropionic acid derivatives
CA2558848C (en) 2004-03-05 2013-11-19 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and pesticide
JP5007788B2 (en) * 2005-05-16 2012-08-22 日産化学工業株式会社 Dihydroazole-substituted benzamide compounds and pest control agents
TWI412322B (en) 2005-12-30 2013-10-21 Du Pont Isoxazolines for controlling invertebrate pests
UY30090A1 (en) 2006-01-16 2007-08-31 Syngenta Participations Ag NEW INSECTICIDES
CN101394742B (en) * 2006-01-16 2012-05-23 先正达参股股份有限公司 Anthranilamide derivatives and their use for the control of insects and acari
TW200808766A (en) * 2006-02-16 2008-02-16 Syngenta Participations Ag Novel insecticides
WO2007125984A1 (en) 2006-04-28 2007-11-08 Nihon Nohyaku Co., Ltd. Isoxazoline derivative, pest-controlling agent, and use of the pest-controlling agent
JP5164525B2 (en) 2006-11-01 2013-03-21 日本曹達株式会社 Nitrogen-containing heterocyclic compounds and pest control agents
EP2155701B1 (en) * 2007-06-13 2013-12-11 E. I. Du Pont de Nemours and Company Isoxazoline insecticides
JP5370772B2 (en) 2007-07-18 2013-12-18 Ｊｓｒ株式会社 Antifouling composition, surface protective film, and method for protecting surface of polarizing plate
JPWO2009072621A1 (en) * 2007-12-07 2011-04-28 日産化学工業株式会社 Substituted dihydroazole compounds and pest control agents
TWI411395B (en) 2007-12-24 2013-10-11 Syngenta Participations Ag Insecticidal compounds
KR20100113598A (en) * 2008-02-07 2010-10-21 바이엘 크롭사이언스 아게 Insecticidal arylpyrrolines
JP2009286773A (en) 2008-03-14 2009-12-10 Bayer Cropscience Ag Insecticidal condensed-ring aryl compounds
CN102131804B (en) * 2008-08-22 2014-12-03 先正达参股股份有限公司 Insecticidal compounds
US8686014B2 (en) 2008-09-04 2014-04-01 Syngenta Limited Insecticidal compounds
WO2010084067A2 (en) 2009-01-22 2010-07-29 Syngenta Participations Ag Insecticidal compounds
US20110288131A1 (en) 2009-01-29 2011-11-24 Syngenta Crop Protection Llc Insecticidal compounds
ES2402887T3 (en) 2009-03-26 2013-05-10 Syngenta Participations Ag Insecticidal compounds
JP2010254629A (en) 2009-04-27 2010-11-11 Bayer Cropscience Ag Optically active azoline derivative
JP2012527414A (en) 2009-05-19 2012-11-08 バイエル・クロップサイエンス・アーゲー Insecticidal arylpyrroline
WO2011054871A1 (en) * 2009-11-06 2011-05-12 Bayer Cropscience Ag Insecticidal arylpyrroline compounds
PT3078664T (en) 2009-12-17 2019-05-31 Boehringer Ingelheim Animal Health Usa Inc Antiparasitic dihydroazole compositions
WO2011073444A2 (en) 2009-12-18 2011-06-23 Basf Se Azoline compounds for combating invertebrate pests
JP2013518084A (en) 2010-02-01 2013-05-20 ビーエーエスエフ ソシエタス・ヨーロピア Substituted ketonic isoxazoline compounds and derivatives for controlling pests
CN102762544B (en) 2010-02-17 2016-03-30 先正达参股股份有限公司 As sterilant isoxazoline derivative
BR112012020941A2 (en) 2010-02-22 2016-06-21 Syngenta Participations Ag dihydrofuran derivatives as insecticide compounds
NZ601446A (en) 2010-02-25 2014-03-28 Syngenta Participations Ag Pesticidal mixtures containing isoxazoline derivatives and insecticide or nematoicidal biological agent
MX2012009707A (en) 2010-02-25 2012-09-12 Syngenta Ltd Process for the preparation of isoxazoline derivatives.
EP2538789A1 (en) 2010-02-25 2013-01-02 Syngenta Participations AG Pesticidal mixtures containing isoxazoline derivatives and a fungicide
JP2011219431A (en) * 2010-04-13 2011-11-04 Bayer Cropscience Ag New aryl nitroalkane derivative
US20130210623A1 (en) 2010-06-09 2013-08-15 Syngenta Crop Protection Llc Pesticidal mixtures including isoxazoline derivatives
EP2579725A2 (en) 2010-06-09 2013-04-17 Syngenta Participations AG Pesticidal mixtures including isoxazoline derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2010149506A1 *

Also Published As

Publication number Publication date
TW201100013A (en) 2011-01-01
JP2012530689A (en) 2012-12-06
KR20120089626A (en) 2012-08-13
US9493445B2 (en) 2016-11-15
US20180065956A1 (en) 2018-03-08
UY32727A (en) 2011-01-31
US8946447B2 (en) 2015-02-03
MX2011013448A (en) 2012-02-13
EA020755B1 (en) 2015-01-30
US20150111944A1 (en) 2015-04-23
BRPI1015931A2 (en) 2015-09-01
MA33372B1 (en) 2012-06-01
HK1163694A1 (en) 2012-09-14
CN102803257A (en) 2012-11-28
CN102803257B (en) 2015-10-14
AU2010264888B2 (en) 2014-07-10
US9834546B2 (en) 2017-12-05
NI201100220A (en) 2012-08-08
CA2764422A1 (en) 2010-12-29
ES2502340T3 (en) 2014-10-03
EA201200031A1 (en) 2012-07-30
AU2010264888A1 (en) 2011-12-22
WO2010149506A1 (en) 2010-12-29
US20130131137A1 (en) 2013-05-23
AR077143A1 (en) 2011-08-03
DOP2011000400A (en) 2012-01-31
US10364235B2 (en) 2019-07-30
CO6480914A2 (en) 2012-07-16
JP5684802B2 (en) 2015-03-18
EP2445906B1 (en) 2014-07-23
US20170022187A1 (en) 2017-01-26
ZA201109217B (en) 2015-08-26
CU20110237A7 (en) 2012-06-21

Similar Documents

Publication Publication Date Title
US10364235B2 (en) Insecticidal compounds
EP2411384B1 (en) Insecticidal compounds
US9282742B2 (en) Insecticidal compounds
EP2331536B1 (en) Insecticidal compounds
EP2331515B1 (en) Insceticidal compounds
EP2238132B1 (en) Insecticidal compounds
US8410145B2 (en) Insecticidal compounds
US20110288131A1 (en) Insecticidal compounds
WO2010084067A2 (en) Insecticidal compounds
WO2008000438A1 (en) Insecticidal compounds
US8455399B2 (en) N-(4-perfluoroalkyl-phenyl)-4-triazolyl-benzamides as insecticides
EP2382208A1 (en) Insecticidal compounds
EP2379541A2 (en) Insecticidal compounds

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20111214

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1163694

Country of ref document: HK

DAX Request for extension of the european patent (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20131021

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 678809

Country of ref document: AT

Kind code of ref document: T

Effective date: 20140815

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602010017715

Country of ref document: DE

Effective date: 20140904

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2502340

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20141003

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

Free format text: REGISTERED BETWEEN 20141023 AND 20141029

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 678809

Country of ref document: AT

Kind code of ref document: T

Effective date: 20140723

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20140723

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141023

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141124

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141024

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141023

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141123

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602010017715

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20150424

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1163694

Country of ref document: HK

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E023614

Country of ref document: HU

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150611

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150630

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150611

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150612

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 8

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140723

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20220623

Year of fee payment: 13

Ref country code: GB

Payment date: 20220526

Year of fee payment: 13

Ref country code: FR

Payment date: 20220517

Year of fee payment: 13

Ref country code: DE

Payment date: 20220512

Year of fee payment: 13

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20220708

Year of fee payment: 13

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602010017715

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20230611